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Antiretroviral bioanalysis methods of tissues and body biofluids

    Robin DiFrancesco

    * Author for correspondence

    HIV Clinical Pharmacology Quality Assurance & HIV Clinical Pharmacology Research Programs, University at Buffalo School of Pharmacy & Pharmaceutical Sciences, Translational Pharmacology Research Core, New York State Center of Excellence in Bioinformatics & Life Sciences, 701 Ellicott Street, Buffalo, NY 14203, USA.

    ,
    Getrude Maduke

    HIV Clinical Pharmacology Quality Assurance & HIV Clinical Pharmacology Research Programs, University at Buffalo School of Pharmacy & Pharmaceutical Sciences, Translational Pharmacology Research Core, New York State Center of Excellence in Bioinformatics & Life Sciences, 701 Ellicott Street, Buffalo, NY 14203, USA

    ,
    Rutva Patel

    HIV Clinical Pharmacology Quality Assurance & HIV Clinical Pharmacology Research Programs, University at Buffalo School of Pharmacy & Pharmaceutical Sciences, Translational Pharmacology Research Core, New York State Center of Excellence in Bioinformatics & Life Sciences, 701 Ellicott Street, Buffalo, NY 14203, USA

    ,
    Charlene R Taylor

    HIV Clinical Pharmacology Quality Assurance & HIV Clinical Pharmacology Research Programs, University at Buffalo School of Pharmacy & Pharmaceutical Sciences, Translational Pharmacology Research Core, New York State Center of Excellence in Bioinformatics & Life Sciences, 701 Ellicott Street, Buffalo, NY 14203, USA

    &
    Gene D Morse

    HIV Clinical Pharmacology Quality Assurance & HIV Clinical Pharmacology Research Programs, University at Buffalo School of Pharmacy & Pharmaceutical Sciences, Translational Pharmacology Research Core, New York State Center of Excellence in Bioinformatics & Life Sciences, 701 Ellicott Street, Buffalo, NY 14203, USA

    Published Online:https://doi.org/10.4155/bio.12.319

    Research in the many areas of HIV treatment, eradication and prevention has necessitated measurement of antiretroviral (ARV) concentrations in nontraditional specimen types. To determine the knowledgebase of critical details for accurate bioanalysis, a review of the literature was performed and summarized. Bioanalytical assays for 31 ARVs, including metabolites, were identified in 205 publications measuring various tissues and biofluids. 18 and 30% of tissue or biofluid methods, respectively, analyzed more than one specimen type; 35–37% of the tissue or biofluid methods quantitated more than one ARV. 20 and 76% of tissue or biofluid methods, respectively, were used for the analysis of human specimens. HPLC methods with UV detection predominated, but chronologically MS detection began to surpass. 40% of the assays provided complete intra- and inter-assay validation data, but only 9% of publications provided any stability data with even less for the prevalent ARV in treatments.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    References

    • Gandhi M, Greenblatt RM. Hair it is: the long and short of monitoring antiretroviral treatment. Ann. Intern. Med.137(8),696–697 (2002).▪ Older method article addressing the measurement of antiretroviral (ARV) in hair. ARV measurement in hair is gaining popularity for adherence applications.
    • Bernard L, Peytavin G, Vuagnat A, De Truchis P, Perronne C. Indinavir concentrations in hair from patients receiving highly active antiretroviral therapy. Lancet352(9142),1757–1758 (1998).
    • Duval X, Peytavin G, Breton G et al. Hair versus plasma concentrations as indicator of indinavir exposure in HIV-1-infected patients treated with indinavir/ritonavir combination. AIDS21(1),106–108 (2007).
    • Gandhi M, Ameli N, Bacchetti P et al. Protease inhibitor levels in hair strongly predict virologic response to treatment. AIDS23(4),471–478 (2009).
    • Huang Y, Gandhi M, Greenblatt RM, Gee W, Lin ET, Messenkoff N. Sensitive analysis of anti-HIV drugs, efavirenz, lopinavir and ritonavir, in human hair by liquid chromatography coupled with tandem mass spectrometry. Rapid Commun. Mass Spectrom.22(21),3401–3409 (2008).
    • Van Heeswijk RP, Veldkamp AI, Mulder JW et al. Saliva as an alternative body fluid for therapeutic drug monitoring of the nonnucleoside reverse transcription inhibitor nevirapine. Ther. Drug Monit.23(3),255–258 (2001).
    • Wintergerst U, Kurowski M, Rolinski B et al. Use of saliva specimens for monitoring indinavir therapy in human immunodeficiency virus-infected patients. Antimicrob. Agents Chemother.44(9),2572–2574 (2000).
    • Letendre S. Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder. Top. Antivir. Med.19(4),137–142 (2011).
    • Hendrix C, Minnis A, Guddera V et al. MTN-001: a phase 2 cross-over study of daily oral and vaginal TFV in healthy, sexually active women results in significantly different product acceptability and vaginal tissue drug concentrations. Presented at: 18th Conference on Retroviruses and Opportunistic Infections. Boston, MA, USA, 27 February–2 March 2011.
    • 10  Kashuba AD, Karim SSA, Kraft E et al. Do systemic and genital tract tenofovir concentrations predict HIV seroconversion in the CAPRISA 004 tenofovir gel trial? Presented at: XVIII International AIDS Conference. Vienna, Austria, 18–23 July 2010.
    • 11  Dicenzo R, Difrancesco R, Cruttenden K, Donnelly J, Schifitto G. Lopinavir cerebrospinal fluid steady-state trough concentrations in HIV-infected adults. Ann. Pharmacother.43(12),1972–1977 (2009).
    • 12  Robbins BL, Nelson SR, Fletcher CV. A novel ultrasensitive LC–MS/MS assay for quantification of intracellular raltegravir in human cell extracts. J. Pharm. Biomed. Anal.70,378–387 (2012).
    • 13  Anderson PL, Zheng JH, King T et al. Concentrations of zidovudine- and lamivudine-triphosphate according to cell type in HIV-seronegative adults. AIDS21(14),1849–1854 (2007).
    • 14  US Department of Health and Human Services, US FDA, Center for Drug Evaluation and Research, Center for Veterinary Medicine. Guidance for Industry: Bioanalytical Method Validation. FDA, Rockville, MD, USA (2001).
    • 15  Estrela Rde C, Ribeiro FS, Barroso PF et al. ABCB1 polymorphisms and the concentrations of lopinavir and ritonavir in blood, semen and saliva of HIV-infected men under antiretroviral therapy. Pharmacogenomics10(2),311–318 (2009).
    • 16  Ghosn J, Chaix ML, Peytavin G et al. Absence of HIV-1 shedding in male genital tract after 1 year of first-line lopinavir/ritonavir alone or in combination with zidovudine/lamivudine. J. Antimicrob. Chemother.61(6),1344–1347 (2008).
    • 17  Rolinski B, Bogner JR, Sadri I, Wintergerst U, Goebel FD. Absorption and elimination kinetics of zidovudine in the cerebrospinal fluid in HIV-1-infected patients. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol.15(3),192–197 (1997).
    • 18  Alcorn J, Mcnamara PJ. Acyclovir, ganciclovir, and zidovudine transfer into rat milk. Antimicrob. Agents Chemother.46(6),1831–1836 (2002).
    • 19  Granda BW, Giancarlo GM, Von Moltke LL, Greenblatt DJ. Analysis of ritonavir in plasma/serum and tissues by high-performance liquid chromatography. J. Pharmacol. Toxicol. Methods40(4),235–239 (1998).
    • 20  Mirochnick M, Thomas T, Capparelli E et al. Antiretroviral concentrations in breast-feeding infants of mothers receiving highly active antiretroviral therapy. Antimicrob. Agents Chemother.53(3),1170–1176 (2009).
    • 21  Shapiro RL, Holland DT, Capparelli E et al. Antiretroviral concentrations in breast-feeding infants of women in Botswana receiving antiretroviral treatment. J. Infect. Dis.192(5),720–727 (2005).
    • 22  Kwara A, Delong A, Rezk N et al. Antiretroviral drug concentrations and HIV RNA in the genital tract of HIV-infected women receiving long-term highly active antiretroviral therapy. Clin. Infect. Dis.46(5),719–725 (2008).
    • 23  Taylor S, Back DJ, Drake SM et al. Antiretroviral drug concentrations in semen of HIV-infected men: differential penetration of indinavir, ritonavir and saquinavir. J. Antimicrob. Chemother.48(3),351–354 (2001).
    • 24  Dumond JB, Yeh RF, Patterson KB et al. Antiretroviral drug exposure in the female genital tract: implications for oral pre- and post-exposure prophylaxis. AIDS21(14),1899–1907 (2007).
    • 25  Burger DM, Rosing H, Ten Napel CH et al. Application of a radioimmunoassay for determination of levels of zalcitabine (ddC) in human plasma, urine, and cerebrospinal fluid. Antimicrob. Agents Chemother.38(12),2763–2767 (1994).
    • 26  Gandhi M, Ameli N, Bacchetti P et al. Atazanavir concentration in hair is the strongest predictor of outcomes on antiretroviral therapy. Clin. Infect. Dis.52(10),1267–1275 (2011).
    • 27  Chu CK, Bhadti VS, Doshi KJ et al. Brain targeting of anti-HIV nucleosides: synthesis and in vitro and in vivo studies of dihydropyridine derivatives of 3’-azido-2’,3’-dideoxyuridine and 3´-azido-3´-deoxythymidine. J. Med. Chem.33(8),2188–2192 (1990).
    • 28  Hamidi M. Central nervous system distribution kinetics of indinavir in rats. J. Pharm. Pharmacol.59(8),1077–1085 (2007).
    • 29  Yilmaz A, Stahle L, Hagberg L, Svennerholm B, Fuchs D, Gisslen M. Cerebrospinal fluid and plasma HIV-1 RNA levels and lopinavir concentrations following lopinavir/ritonavir regimen. Scand. J. Infect. Dis.36(11–12),823–828 (2004).
    • 30  Gisolf EH, Enting RH, Jurriaans S et al. Cerebrospinal fluid HIV-1 RNA during treatment with ritonavir/saquinavir or ritonavir/saquinavir/stavudine. AIDS14(11),1583–1589 (2000).
    • 31  Yilmaz A, Fuchs D, Hagberg L et al. Cerebrospinal fluid HIV-1 RNA, intrathecal immunoactivation, and drug concentrations after treatment with a combination of saquinavir, nelfinavir, and two nucleoside analogues: the M61022 study. BMC Infect. Dis.6,63 (2006).
    • 32  Kravcik S, Gallicano K, Roth V et al. Cerebrospinal fluid HIV RNA and drug levels with combination ritonavir and saquinavir. J. Acquir. Immune Defic. Syndr.21(5),371–375 (1999).
    • 33  Tashima KT, Caliendo AM, Ahmad M et al. Cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) suppression and efavirenz drug concentrations in HIV-1-infected patients receiving combination therapy. J. Infect. Dis.180(3),862–864 (1999).
    • 34  Yilmaz A, Watson V, Else L, Gisslen M. Cerebrospinal fluid maraviroc concentrations in HIV-1 infected patients. AIDS23(18),2537–2540 (2009).
    • 35  Doshi KJ, Gallo JM, Boudinot FD, Schinazi RF, Chu CK. Comparative pharmacokinetics of 3’-azido-3’-deoxythymidine (AZT) and 3’-azido-2’,3’-dideoxyuridine (AZddU) in mice. Drug Metab. Dispos.17(6),590–594 (1989).
    • 36  Lupia RH, Ferencz N, Lertora JJ, Aggarwal SK, George WJ, Agrawal KC. Comparative pharmacokinetics of two prodrugs of zidovudine in rabbits: enhanced levels of zidovudine in brain tissue. Antimicrob. Agents Chemother.37(4),818–824 (1993).
    • 37  Taylor S, Van Heeswijk RP, Hoetelmans RM et al. Concentrations of nevirapine, lamivudine and stavudine in semen of HIV-1-infected men. AIDS14(13),1979–1984 (2000).
    • 38  Chan DJ, Ray JE, Mcnally L, Batterham M, Smith DE. Correlation between HIV-1 RNA load in blood and seminal plasma depending on antiretroviral treatment status, regimen and penetration of semen by antiretroviral drugs. Curr. HIV Res.6(5),477–484 (2008).
    • 39  Taylor S, Jayasuriya AN, Berry A et al. Darunavir concentrations exceed the protein-corrected EC(5)(0) for wild-type HIV in the semen of HIV-1-infected men. AIDS24(16),2583–2587 (2010).
    • 40  Yilmaz A, Izadkhashti A, Price RW et al. Darunavir concentrations in cerebrospinal fluid and blood in HIV-1-infected individuals. AIDS Res. Hum. Retroviruses25(4),457–461 (2009).
    • 41  Patterson K, Jennings S, Falcon R, Mrus J, Kashuba A. Darunavir, ritonavir, and etravirine pharmacokinetics in the cervicovaginal fluid and blood plasma of HIV-infected women. Antimicrob. Agents Chemother.55(3),1120–1122 (2011).
    • 42  Anderson BD, May MJ, Jordan S, Song L, Roberts MJ, Leggas M. Dependence of nelfinavir brain uptake on dose and tissue concentrations of the selective P-glycoprotein inhibitor zosuquidar in rats. Drug Metab. Dispos.34(4),653–659 (2006).
    • 43  Ding Y, Williamson LN, White CA, Bartlett MG. Determination of 2’,3’-dideoxycytidine in maternal plasma, amniotic fluid, placental and fetal tissues by high-performance liquid chromatography. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.811(2),183–189 (2004).
    • 44  Clark TN, White CA, Chu CK, Bartlett MG. Determination of 3’-azido-2’,3’-dideoxyuridine in maternal plasma, amniotic fluid, fetal and placental tissues by high-performance liquid chromatography. J. Chromatogr. B Biomed. Sci. Appl.755(1–2),165–172 (2001).
    • 45  Clark TN, White CA, Bartlett MG. Determination of Abacavir in maternal plasma, amniotic fluid, fetal and placental tissues by a polarity switching liquid chromatography/tandem mass spectrometry method. Rapid Commun. Mass Spectrom.18(4),405–411 (2004).
    • 46  Pereira AS, Kenney KB, Cohen MS, Eron JJ, Tidwell RR, Dunn JA. Determination of amprenavir, a HIV-1 protease inhibitor, in human seminal plasma using high-performance liquid chromatography–tandem mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.766(2),307–317 (2002).
    • 47  Clark TN, White CA, Bartlett MG. Determination of didanosine in maternal plasma, amniotic fluid, fetal and placental tissues by high-performance liquid chromatography–tandem mass spectrometry. Biomed. Chromatogr.20(6–7),605–611 (2006).
    • 48  Zhong L, Yeh KC. Determination of indinavir in human cerebrospinal fluid and plasma by solid-phase extraction and high-performance liquid chromatography with column switching. J. Chromatogr. B Biomed. Sci. Appl.734(1),63–71 (1999).
    • 49  Alnouti Y, White CA, Bartlett MG. Determination of lamivudine in plasma, amniotic fluid, and rat tissues by liquid chromatography. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.803(2),279–284 (2004).
    • 50  Estrela RC, Ribeiro FS, Seixas BV, Suarez-Kurtz G. Determination of lopinavir and ritonavir in blood plasma, seminal plasma, saliva and plasma ultra-filtrate by liquid chromatography/tandem mass spectrometry detection. Rapid Commun. Mass Spectrom.22(5),657–664 (2008).
    • 51  Difrancesco R, Dicenzo R, Vicente G et al. Determination of lopinavir cerebral spinal fluid and plasma ultrafiltrate concentrations by liquid chromatography coupled to tandem mass spectrometry. J. Pharm. Biomed. Anal.44(5),1139–1146 (2007).▪ Example article that normalized biofluid (cerebrospinal fluid) results using protein content of the sample.
    • 52  Theron A, Cromarty D, Rheeders M, Viljoen M. Determination of salivary efavirenz by liquid chromatography coupled with tandem mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.878(28),2886–2890 (2010).
    • 53  Hoetelmans RM, Van Essenberg M, Meenhorst PL, Mulder JW, Beijnen JH. Determination of saquinavir in human plasma, saliva, and cerebrospinal fluid by ion-pair high-performance liquid chromatography with ultraviolet detection. J. Chromatogr. B Biomed. Sci. Appl.698(1–2),235–241 (1997).
    • 54  Rezk NL, Abdel-Megeed MF, Kashuba AD. Development of a highly efficient extraction technique and specific multiplex assay for measuring antiretroviral drug concentrations in breast milk. Ther. Drug Monit.29(4),429–436 (2007).
    • 55  Choi SO, Rezk N, Kim JS, Kashuba AD. Development of an LC–MS method for measuring TNF in human vaginal tissue. J. Chromatogr. Sci.48(3),219–223 (2010).
    • 56  Deremer M, D’ambrosio R, Morse GD. Didanosine measurement by radioimmunoassay. Antimicrob. Agents Chemother.40(6),1331–1334 (1996).
    • 57  Lafeuillade A, Solas C, Halfon P, Chadapaud S, Hittinger G, Lacarelle B. Differences in the detection of three HIV-1 protease inhibitors in non-blood compartments: clinical correlations. HIV Clin. Trials3(1),27–35 (2002).
    • 58  Launay O, Tod M, Louchahi K et al. Differential diffusions of indinavir and lopinavir in genital secretions of human immunodeficiency virus-infected women. Antimicrob. Agents Chemother.48(2),632–634 (2004).
    • 59  Dumond JB, Reddy YS, Troiani L et al. Differential extracellular and intracellular concentrations of zidovudine and lamivudine in semen and plasma of HIV-1-infected men. J. Acquir. Immune Defic. Syndr.48(2),156–162 (2008).
    • 60  Yajima T, Juni K, Saneyoshi M, Hasegawa T, Kawaguchi T. Direct transport of 2’,3’-didehydro-3’-deoxythymidine (D4T) and its ester derivatives to the cerebrospinal fluid via the nasal mucous membrane in rats. Biol. Pharm. Bull.21(3),272–277 (1998).
    • 61  Lorello G, La Porte C, Pilon R, Zhang G, Karnauchow T, Macpherson P. Discordance in HIV-1 viral loads and antiretroviral drug concentrations comparing semen and blood plasma. HIV Med.10(9),548–554 (2009).
    • 62  Solas C, Lafeuillade A, Halfon P, Chadapaud S, Hittinger G, Lacarelle B. Discrepancies between protease inhibitor concentrations and viral load in reservoirs and sanctuary sites in human immunodeficiency virus-infected patients. Antimicrob. Agents Chemother.47(1),238–243 (2003).▪▪ Describes the measurement of ARV concentrations in biofluids and tissues and relates these concentrations to HIV viral changes. The same approach will be followed as eradication and new ARV site-targeted formulations are researched.
    • 63  Washington CB, Wiltshire HR, Man M et al. The disposition of saquinavir in normal and P-glycoprotein deficient mice, rats, and in cultured cells. Drug Metab. Dispos.28(9),1058–1062 (2000).
    • 64  Takasawa K, Terasaki T, Suzuki H, Ooie T, Sugiyama Y. Distributed model analysis of 3’-azido-3’-deoxythymidine and 2’,3’-dideoxyinosine distribution in brain tissue and cerebrospinal fluid. J. Pharmacol. Exp. Ther.282(3),1509–1517 (1997).
    • 65  Wong SL, Van Belle K, Sawchuk RJ. Distributional transport kinetics of zidovudine between plasma and brain extracellular fluid/cerebrospinal fluid in the rabbit: investigation of the inhibitory effect of probenecid utilizing microdialysis. J. Pharmacol. Exp. Ther.264(2),899–909 (1993).
    • 66  Jordan HL, Pereira AS, Cohen MS, Kashuba AD. Domestic cat model for predicting human nucleoside analogue pharmacokinetics in blood and seminal plasma. Antimicrob. Agents Chemother.45(7),2173–2176 (2001).
    • 67  Hoesterey BL, Galinsky RE, Anderson BD. Dose dependence in the plasma pharmacokinetics and uptake kinetics of 2’,3’-dideoxyinosine into brain and cerebrospinal fluid of rats. Drug Metab. Dispos.19(5),907–912 (1991).
    • 68  Best BM, Koopmans PP, Letendre SL et al. Efavirenz concentrations in CSF exceed IC50 for wild-type HIV. J. Antimicrob. Chemother.66(2),354–357 (2011).
    • 69  Colebunders R, Hodossy B, Burger D et al. The effect of highly active antiretroviral treatment on viral load and antiretroviral drug levels in breast milk. AIDS19(16),1912–1915 (2005).
    • 70  Khaliq Y, Gallicano K, Venance S, Kravcik S, Cameron DW. Effect of ketoconazole on ritonavir and saquinavir concentrations in plasma and cerebrospinal fluid from patients infected with human immunodeficiency virus. Clin. Pharmacol. Ther.68(6),637–646 (2000).
    • 71  Tuntland T, Nosbisch C, Unadkat JD. Effect of pregnancy, mode of administration and neonatal age on the pharmacokinetics of zalcitabine (2’, 3’-dideoxycytidine) in the pigtailed macaque (Macaca nemestrina). J. Antimicrob. Chemother.40(5),687–693 (1997).
    • 72  Cao YJ, Ndovi TT, Parsons TL, Guidos AM, Caffo B, Hendrix CW. Effect of semen sampling frequency on seminal antiretroviral drug concentration. Clin. Pharmacol. Ther.83(6),848–856 (2008).
    • 73  Pereira CM, Nosbisch C, Baughman WL, Unadkat JD. Effect of zidovudine on transplacental pharmacokinetics of ddI in the pigtailed macaque (Macaca nemestrina). Antimicrob. Agents Chemother.39(2),343–345 (1995).
    • 74  Chaudry NI, Eron JJ, Naderer OJ et al. Effects of formulation and dosing strategy on amprenavir concentrations in the seminal plasma of human immunodeficiency virus type 1-infected men. Clin. Infect. Dis.35(6),760–762 (2002).
    • 75  Haas DW, Johnson B, Nicotera J et al. Effects of ritonavir on indinavir pharmacokinetics in cerebrospinal fluid and plasma. Antimicrob. Agents Chemother.47(7),2131–2137 (2003).
    • 76  Antinori A, Perno CF, Giancola ML et al. Efficacy of cerebrospinal fluid (CSF)-penetrating antiretroviral drugs against HIV in the neurological compartment: different patterns of phenotypic resistance in CSF and plasma. Clin. Infect. Dis.41(12),1787–1793 (2005).
    • 77  Karlstrom O, Stahle L, Perrin L, Tegude H, Sonnerborg A. Efficacy of nelfinavir-based treatment in the central nervous system of HIV-1 infected patients. Scand. J. Infect. Dis.38(5),371–374 (2006).
    • 78  Gehrig AK, Mikus G, Haefeli WE, Burhenne J. Electrospray tandem mass spectroscopic characterisation of 18 antiretroviral drugs and simultaneous quantification of 12 antiretrovirals in plasma. Rapid Commun. Mass Spectrom.21(16),2704–2716 (2007).
    • 79  Hudelson SE, Mcconnell MS, Bagenda D et al. Emergence and persistence of nevirapine resistance in breast milk after single-dose nevirapine administration. AIDS24(4),557–561 (2010).
    • 80  Van Praag RM, Weverling GJ, Portegies P et al. Enhanced penetration of indinavir in cerebrospinal fluid and semen after the addition of low-dose ritonavir. AIDS14(9),1187–1194 (2000).
    • 81  Brewster ME, Anderson WR, Webb AI et al. Evaluation of a brain-targeting zidovudine chemical delivery system in dogs. Antimicrob. Agents Chemother.41(1),122–128 (1997).
    • 82  Rolinski B, Wintergerst U, Matuschke A et al. Evaluation of saliva as a specimen for monitoring zidovudine therapy in HIV-infected patients. AIDS5(7),885–888 (1991).
    • 83  Aweeka F, Jayewardene A, Staprans S et al. Failure to detect nelfinavir in the cerebrospinal fluid of HIV-1–infected patients with and without AIDS dementia complex. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol.20(1),39–43 (1999).
    • 84  Edwards JE, Brouwer KR, Mcnamara PJ. GF120918, a P-glycoprotein modulator, increases the concentration of unbound amprenavir in the central nervous system in rats. Antimicrob. Agents Chemother.46(7),2284–2286 (2002).
    • 85  Salado-Rasmussen K, Theilgaard ZP, Chiduo M, Pedersen C, Gerstoft J, Katzenstein TL. Good performance of an immunoassay based method for nevirapine measurements in human breast milk. Clin. Chem. Lab. Med.49(7),1171–1175 (2011).
    • 86  Barau C, Delaugerre C, Braun J et al. High concentration of raltegravir in semen of HIV-infected men: results from a substudy of the EASIER-ANRS 138 trial. Antimicrob. Agents Chemother.54(2),937–939 (2010).
    • 87  Burhenne J, Riedel KD, Martin-Facklam M, Mikus G, Haefeli WE. Highly sensitive determination of saquinavir in biological samples using liquid chromatography–tandem mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.784(2),233–242 (2003).
    • 88  Avery LB, Parsons TL, Meyers DJ, Hubbard WC. A highly sensitive ultra performance liquid chromatography–tandem mass spectrometric (UPLC–MS/MS) technique for quantitation of protein free and bound efavirenz (EFV) in human seminal and blood plasma. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.878(31),3217–3224 (2010).
    • 89  Hoetelmans RM, Van Essenberg M, Profijt M, Meenhorst PL, Mulder JW, Beijnen JH. High-performance liquid chromatographic determination of ritonavir in human plasma, cerebrospinal fluid and saliva. J. Chromatogr. B Biomed. Sci. Appl.705(1),119–126 (1998).
    • 90  Lafeuillade A, Solas C, Chadapaud S, Hittinger G, Poggi C, Lacarelle B. HIV-1 RNA levels, resistance, and drug diffusion in semen versus blood in patients receiving a lopinavir-containing regimen. J. Acquir. Immune Defic. Syndr.32(4),462–464 (2003).
    • 91  Mudigonda K, Jukanti R, Apte SS et al. HPLC quantification of the HIV-1 protease inhibitor saquinavir in brain and testis of mice. Biomed. Chromatogr.20(10),1028–1032 (2006).
    • 92  Pav JW, Rowland LS, Korpalski DJ. HPLC–UV method for the quantitation of nevirapine in biological matrices following solid phase extraction. J. Pharm. Biomed. Anal.20(1–2),91–98 (1999).
    • 93  Salama NN, Kelly EJ, Bui T, Ho RJ. The impact of pharmacologic and genetic knockout of P-glycoprotein on nelfinavir levels in the brain and other tissues in mice. J. Pharm. Sci.94(6),1216–1225 (2005).
    • 94  Namane A, Gouyette C, Fillion MP, Fillion G, Huynh-Dinh T. Improved brain delivery of AZT using a glycosyl phosphotriester prodrug. J. Med. Chem.35(16),3039–3044 (1992).
    • 95  Tuntland T, Odinecs A, Pereira CM, Nosbisch C, Unadkat JD. In vitro models to predict the in vivo mechanism, rate, and extent of placental transfer of dideoxynucleoside drugs against human immunodeficiency virus. Am. J. Obstet. Gynecol.180(1 Pt 1),198–206 (1999).
    • 96  Ndesendo VM, Pillay V, Choonara YE et al.In vivo evaluation of the release of zidovudine and polystyrene sulfonate from a dual intravaginal bioadhesive polymeric device in the pig model. J. Pharm. Sci.100(4),1416–1435 (2011).
    • 97  Takasawa K, Terasaki T, Suzuki H, Sugiyama Y. In vivo evidence for carrier-mediated efflux transport of 3’-azido-3’-deoxythymidine and 2’,3’-dideoxyinosine across the blood-brain barrier via a probenecid-sensitive transport system. J. Pharmacol. Exp. Ther.281(1),369–375 (1997).
    • 98  Odinecs A, Nosbisch C, Keller RD, Baughman WL, Unadkat JD. In vivo maternal–fetal pharmacokinetics of stavudine (2’,3’-didehydro-3’-deoxythymidine) in pigtailed macaques (Macaca nemestrina). Antimicrob. Agents Chemother.40(1),196–202 (1996).
    • 99  Tuntland T, Odinecs A, Nosbisch C, Unadkat JD. In vivo maternal–fetal-amniotic fluid pharmacokinetics of zidovudine in the pigtailed macaque: comparison of steady-state and single-dose regimens. J. Pharmacol. Exp. Ther.285(1),54–62 (1998).
    • 100  Chow HH, Li P, Brookshier G, Tang Y. In vivo tissue disposition of 3’-azido-3’-deoxythymidine and its anabolites in control and retrovirus-infected mice. Drug Metab. Dispos.25(4),412–422 (1997).
    • 101  Poirier MC, Patterson TA, Slikker W Jr, Olivero OA. Incorporation of 3’-azido-3’-deoxythymidine (AZT) into fetal DNA and fetal tissue distribution of drug after infusion of pregnant late-term rhesus macaques with a human-equivalent AZT dose. J. Acquir. Immune Defic. Syndr.22(5),477–483 (1999).
    • 102  Stahle L, Martin C, Svensson JO, Sonnerborg A. Indinavir in cerebrospinal fluid of HIV-1-infected patients. Lancet350(9094),1823 (1997).
    • 103  Letendre SL, Capparelli EV, Ellis RJ, Mccutchan JA. Indinavir population pharmacokinetics in plasma and cerebrospinal fluid. The HIV Neurobehavioral Research Center Group. Antimicrob. Agents Chemother.44(8),2173–2175 (2000).
    • 104  Martin C, Sonnerborg A, Svensson JO, Stahle L. Indinavir-based treatment of HIV-1 infected patients: efficacy in the central nervous system. AIDS13(10),1227–1232 (1999).
    • 105  Kaddoumi A, Choi SU, Kinman L et al. Inhibition of P-glycoprotein activity at the primate blood-brain barrier increases the distribution of nelfinavir into the brain but not into the cerebrospinal fluid. Drug Metab. Dispos.35(9),1459–1462 (2007).
    • 106  Giri N, Shaik N, Pan G et al. Investigation of the role of breast cancer resistance protein (Bcrp/Abcg2) on pharmacokinetics and central nervous system penetration of abacavir and zidovudine in the mouse. Drug Metab. Dispos.36(8),1476–1484 (2008).
    • 107  Lewis LL, Venzon D, Church J et al. Lamivudine in children with human immunodeficiency virus infection: a Phase I/II study. The National Cancer Institute Pediatric Branch-Human Immunodeficiency Virus Working Group. J. Infect. Dis.174(1),16–25 (1996).
    • 108  Brewer E, Felix T, Clarke P, Edgington A, Muirhead D. An LC–MS/MS method for quantitative determination of maraviroc (UK-427,857) in human plasma, urine and cerebrospinal fluid. Biomed. Chromatogr.24(12),1316–1323 (2010).
    • 109  Vergara TR, Estrela RC, Suarez-Kurtz G, Schechter M, Cerbino-Neto J, Barroso PF. Limited penetration of lopinavir and ritonavir in the genital tract of men infected with HIV-1 in Brazil. Ther. Drug Monit.28(2),175–179 (2006).
    • 110  Sankatsing SU, Droste J, Burger D et al. Limited penetration of lopinavir into seminal plasma of HIV-1-infected men. AIDS16(12),1698–1700 (2002).
    • 111  Kinman L, Brodie SJ, Tsai CC et al. Lipid-drug association enhanced HIV-1 protease inhibitor indinavir localization in lymphoid tissues and viral load reduction: a proof of concept study in HIV-2287-infected macaques. J. Acquir. Immune Defic. Syndr.34(4),387–397 (2003).
    • 112  Huang Y, Zurlinden E, Lin E et al. Liquid chromatographic–tandem mass spectrometric assay for the simultaneous determination of didanosine and stavudine in human plasma, bronchoalveolar lavage fluid, alveolar cells, peripheral blood mononuclear cells, seminal plasma, cerebrospinal fluid and tonsil tissue. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.799(1),51–61 (2004).
    • 113  Capparelli EV, Holland D, Okamoto C et al. Lopinavir concentrations in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV. AIDS19(9),949–952 (2005).
    • 114  Isaac A, Taylor S, Cane P et al. Lopinavir/ritonavir combined with twice-daily 400 mg indinavir: pharmacokinetics and pharmacodynamics in blood, CSF and semen. J. Antimicrob. Chemother.54(2),498–502 (2004).
    • 115  Van Zyl GU, Van Mens TE, Mcilleron H et al. Low lopinavir plasma or hair concentrations explain second-line protease inhibitor failures in a resource-limited setting. J. Acquir. Immune Defic. Syndr.56(4),333–339 (2011).
    • 116  Desormeaux A, Bergeron MG. Lymphoid tissue targeting of anti-HIV drugs using liposomes. Meth. Enzymol.391,330–351 (2005).
    • 117  Zhang L, Price R, Aweeka F, Bellibas SE, Sheiner LB. Making the most of sparse clinical data by using a predictive-model-based analysis, illustrated with a stavudine pharmacokinetic study. Eur. J. Pharm. Sci.12(4),377–385 (2001).
    • 118  Dumond JB, Patterson KB, Pecha AL et al. Maraviroc concentrates in the cervicovaginal fluid and vaginal tissue of HIV-negative women. J. Acquir. Immune Defic. Syndr.51(5),546–553 (2009).
    • 119  Tiraboschi JM, Niubo J, Curto J, Podzamczer D. Maraviroc concentrations in cerebrospinal fluid in HIV-infected patients. J. Acquir. Immune Defic. Syndr.55(5),606–609 (2010).
    • 120  Huang CS, Boudinot FD, Feldman S. Maternal–fetal pharmacokinetics of zidovudine in rats. J. Pharm. Sci.85(9),965–970 (1996).
    • 121  Mandelbrot L, Peytavin G, Firtion G, Farinotti R. Maternal–fetal transfer and amniotic fluid accumulation of lamivudine in human immunodeficiency virus-infected pregnant women. Am. J. Obstet. Gynecol.184(2),153–158 (2001).
    • 122  Chappuy H, Treluyer JM, Jullien V et al. Maternal–fetal transfer and amniotic fluid accumulation of nucleoside analogue reverse transcriptase inhibitors in human immunodeficiency virus-infected pregnant women. Antimicrob. Agents Chemother.48(11),4332–4336 (2004).
    • 123  Sadler BM, Chittick GE, Polk RE et al. Metabolic disposition and pharmacokinetics of [14C]-amprenavir, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, administered as a single oral dose to healthy male subjects. J. Clin. Pharmacol.41(4),386–396 (2001).
    • 124  Yang Z, Huang Y, Gan G, Sawchuk RJ. Microdialysis evaluation of the brain distribution of stavudine following intranasal and intravenous administration to rats. J. Pharm. Sci.94(7),1577–1588 (2005).
    • 125  Yang Z, Brundage RC, Barbhaiya RH, Sawchuk RJ. Microdialysis studies of the distribution of stavudine into the central nervous system in the freely-moving rat. Pharm. Res.14(7),865–872 (1997).
    • 126  Mcdowell JA, Lou Y, Symonds WS, Stein DS. Multiple-dose pharmacokinetics and pharmacodynamics of abacavir alone and in combination with zidovudine in human immunodeficiency virus-infected adults. Antimicrob. Agents Chemother.44(8),2061–2067 (2000).
    • 127  Seki T, Sato N, Hasegawa T, Kawaguchi T, Juni K. Nasal absorption of zidovudine and its transport to cerebrospinal fluid in rats. Biol. Pharm. Bull.17(8),1135–1137 (1994).
    • 128  Yarchoan R, Mitsuya H, Pluda JM et al. The National Cancer Institute Phase I study of 2’,3’-dideoxyinosine administration in adults with AIDS or AIDS-related complex: analysis of activity and toxicity profiles. Rev. Infect. Dis.12(Suppl. 5),S522–S533 (1990).
    • 129  Rakhmanina NY, Capparelli EV, Van Den Anker JN et al. Nevirapine concentration in nonstimulated saliva: an alternative to plasma sampling in children with human immunodeficiency virus infection. Ther. Drug Monit.29(1),110–117 (2007).
    • 130  Bennetto-Hood C, Johnson VA, King JR, Hoesley CJ, Acosta EP. Novel methodology for antiretroviral quantitation in the female genital tract. HIV Clin. Trials10(3),193–199 (2009).
    • 131  Pereira AS, Kashuba AD, Fiscus SA et al. Nucleoside analogues achieve high concentrations in seminal plasma: relationship between drug concentration and virus burden. J. Infect. Dis.180(6),2039–2043 (1999).
    • 132  Kinman L, Bui T, Larsen K et al. Optimization of lipid-indinavir complexes for localization in lymphoid tissues of HIV-infected macaques. J. Acquir. Immune Defic. Syndr.42(2),155–161 (2006).
    • 133  Hoetelmans RM, Kraaijeveld CL, Meenhorst PL et al. Penetration of 3’-amino-3’-deoxythymidine, a cytotoxic metabolite of zidovudine, into the cerebrospinal fluid of HIV-1-infected patients. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol.15(2),131–136 (1997).
    • 134  Van Leeuwen E, Ter Heine R, Van Der Veen F, Repping S, Beijnen JH, Prins JM. Penetration of atazanavir in seminal plasma of men infected with human immunodeficiency virus type 1. Antimicrob. Agents Chemother.51(1),335–337 (2007).
    • 135  Cruciani M, Liuzzi G, Chirianni A et al. Penetration of didanosine in semen of HIV-1-infected men. J. Antimicrob. Chemother.57(6),1244–1247 (2006).
    • 136  Taylor S, Reynolds H, Sabin CA et al. Penetration of efavirenz into the male genital tract: drug concentrations and antiviral activity in semen and blood of HIV-1-infected men. AIDS15(15),2051–2053 (2001).
    • 137  Ghosn J, Chaix ML, Peytavin G et al. Penetration of enfuvirtide, tenofovir, efavirenz, and protease inhibitors in the genital tract of HIV-1-infected men. AIDS18(14),1958–1961 (2004).
    • 138  Van Praag RM, Van Heeswijk RP, Jurriaans S, Lange JM, Hoetelmans RM, Prins JM. Penetration of the nucleoside analogue abacavir into the genital tract of men infected with human immunodeficiency virus type 1. Clin. Infect. Dis.33(8),e91–e92 (2001).
    • 139  Ljungdahl-Stahle E, Guzenda E, Bottiger D, Wahren B, Oberg B, Stahle L. Penetration of zidovudine and 3’-fluoro-3’-deoxythymidine into the brain, muscle tissue, and veins in cynomolgus monkeys: relation to antiviral action. Antimicrob. Agents Chemother.36(11),2418–2422 (1992).
    • 140  Burger DM, Kraaijeveld CL, Meenhorst PL et al. Penetration of zidovudine into the cerebrospinal fluid of patients infected with HIV. AIDS7(12),1581–1587 (1993).
    • 141  Kunz A, Frank M, Mugenyi K et al. Persistence of nevirapine in breast milk and plasma of mothers and their children after single-dose administration. J. Antimicrob. Chemother.63(1),170–177 (2009).
    • 142  Shaik N, Giri N, Pan G, Elmquist WF. P-glycoprotein-mediated active efflux of the anti-HIV1 nucleoside abacavir limits cellular accumulation and brain distribution. Drug Metab. Dispos.35(11),2076–2085 (2007).
    • 143  Reddy YS, Gotzkowsky SK, Eron JJ et al. Pharmacokinetic and pharmacodynamic investigation of efavirenz in the semen and blood of human immunodeficiency virus type 1-infected men. J. Infect. Dis.186(9),1339–1343 (2002).
    • 144  Boal JH, Plessinger MA, Van Den Reydt C, Miller RK. Pharmacokinetic and toxicity studies of AZT (zidovudine) following perfusion of human term placenta for 14 hours. Toxicol. Appl. Pharmacol.143(1),13–21 (1997).
    • 145  Hirt D, Urien S, Jullien V et al. Pharmacokinetic modelling of the placental transfer of nelfinavir and its M8 metabolite: a population study using 75 maternal-cord plasma samples. Br. J. Clin. Pharmacol.64(5),634–644 (2007).
    • 146  Van Praag RM, Repping S, De Vries JW, Lange JM, Hoetelmans RM, Prins JM. Pharmacokinetic profiles of nevirapine and indinavir in various fractions of seminal plasma. Antimicrob. Agents Chemother.45(10),2902–2907 (2001).
    • 147  Moodley J, Moodley D, Pillay K et al. Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring. J. Infect. Dis.178(5),1327–1333 (1998).
    • 148  Borg N, Stahle L. Pharmacokinetics and distribution over the blood-brain barrier of zalcitabine (2’,3’-dideoxycytidine) and BEA005 (2’, 3’-dideoxy-3’-hydroxymethylcytidine) in rats, studied by microdialysis. Antimicrob. Agents Chemother.42(9),2174–2177 (1998).
    • 149  Schinazi RF, Boudinot FD, Ibrahim SS, Manning C, Mcclure HM, Liotta DC. Pharmacokinetics and metabolism of racemic 2’,3’-dideoxy-5-fluoro-3’-thiacytidine in rhesus monkeys. Antimicrob. Agents Chemother.36(11),2432–2438 (1992).
    • 150  Jin SX, Bi DZ, Wang J, Wang YZ, Hu HG, Deng YH. Pharmacokinetics and tissue distribution of zidovudine in rats following intravenous administration of zidovudine myristate loaded liposomes. Pharmazie60(11),840–843 (2005).
    • 151  Hartman NR, Yarchoan R, Pluda JM et al. Pharmacokinetics of 2’,3’-dideoxyadenosine and 2’,3’-dideoxyinosine in patients with severe human immunodeficiency virus infection. Clin. Pharmacol. Ther.47(5),647–654 (1990).
    • 152  Pereira AS, Smeaton LM, Gerber JG et al. The pharmacokinetics of amprenavir, zidovudine, and lamivudine in the genital tracts of men infected with human immunodeficiency virus type 1 (AIDS clinical trials group study 850). J. Infect. Dis.186(2),198–204 (2002).
    • 153  Hawkins ME, Mitsuya H, Mccully CM et al. Pharmacokinetics of dideoxypurine nucleoside analogs in plasma and cerebrospinal fluid of rhesus monkeys. Antimicrob. Agents Chemother.39(6),1259–1264 (1995).
    • 154  Sugioka N, Haraya K, Maeda Y, Fukushima K, Takada K. Pharmacokinetics of human immunodeficiency virus protease inhibitor, nelfinavir, in poloxamer 407-induced hyperlipidemic model rats. Biol. Pharm. Bull.32(2),269–275 (2009).
    • 155  Brown SD, Bartlett MG, White CA. Pharmacokinetics of intravenous acyclovir, zidovudine, and acyclovir-zidovudine in pregnant rats. Antimicrob. Agents Chemother.47(3),991–996 (2003).
    • 156  Blaney SM, Daniel MJ, Harker AJ, Godwin K, Balis FM. Pharmacokinetics of lamivudine and BCH-189 in plasma and cerebrospinal fluid of nonhuman primates. Antimicrob. Agents Chemother.39(12),2779–2782 (1995).
    • 157  Mirochnick M, Fenton T, Gagnier P et al. Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Pediatric AIDS Clinical Trials Group Protocol 250 Team. J. Infect. Dis.178(2),368–374 (1998).
    • 158  Van Rompay KK, Hamilton M, Kearney B, Bischofberger N. Pharmacokinetics of tenofovir in breast milk of lactating rhesus macaques. Antimicrob. Agents Chemother.49(5),2093–2094 (2005).
    • 159  Balis FM, Pizzo PA, Murphy RF et al. The pharmacokinetics of zidovudine administered by continuous infusion in children. Ann. Intern. Med.110(4),279–285 (1989).
    • 160  Kline MW, Dunkle LM, Church JA et al. A Phase I/II evaluation of stavudine (d4T) in children with human immunodeficiency virus infection. Pediatrics96(2 Pt 1),247–252 (1995).
    • 161  Musoke P, Guay LA, Bagenda D et al. A Phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006). AIDS13(4),479–486 (1999).
    • 162  Gingelmaier A, Kurowski M, Kastner R et al. Placental transfer and pharmacokinetics of lopinavir and other protease inhibitors in combination with nevirapine at delivery. AIDS20(13),1737–1743 (2006).
    • 163  Siu SS, Yeung JH, Pang MW, Chiu PY, Lau TK. Placental transfer of Zidovudine in first trimester of pregnancy. Obstet. Gynecol.106(4),824–827 (2005).
    • 164  Moyle GJ, Sadler M, Buss N. Plasma and cerebrospinal fluid saquinavir concentrations in patients receiving combination antiretroviral therapy. Clin. Infect. Dis.28(2),403–404 (1999).
    • 165  Zhou XJ, Havlir DV, Richman DD et al. Plasma population pharmacokinetics and penetration into cerebrospinal fluid of indinavir in combination with zidovudine and lamivudine in HIV-1-infected patients. AIDS14(18),2869–2876 (2000).
    • 166  Ved PM, Kim K. Poly(ethylene oxide/propylene oxide) copolymer thermo-reversible gelling system for the enhancement of intranasal zidovudine delivery to the brain. Int. J. Pharm.411(1–2),1–9 (2011).
    • 167  Taylor S, Back DJ, Workman J et al. Poor penetration of the male genital tract by HIV-1 protease inhibitors. AIDS13(7),859–860 (1999).
    • 168  Walker DK, Bowers SJ, Mitchell RJ, Potchoiba MJ, Schroeder CM, Small HF. Preclinical assessment of the distribution of maraviroc to potential human immunodeficiency virus (HIV) sanctuary sites in the central nervous system (CNS) and gut-associated lymphoid tissue (GALT). Xenobiotica38(10),1330–1339 (2008).
    • 169  Galinsky RE, Flaharty KK, Hoesterey BL, Anderson BD. Probenecid enhances central nervous system uptake of 2’,3’-dideoxyinosine by inhibiting cerebrospinal fluid efflux. J. Pharmacol. Exp. Ther.257(3),972–978 (1991).
    • 170  Talameh JA, Rezk NL, Kashuba AD. Quantifying the HIV-1 integrase inhibitor raltegravir in female genital tract secretions using high-performance liquid chromatography with ultraviolet detection. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.878(1),92–96 (2010).
    • 171  Hoetelmans RM, Profijt M, Mennhorst PL, Mulder JW, Beijnen JH. Quantitative determination of (-)-2’-deoxy-3’-thiacytidine (lamivudine) in human plasma, saliva and cerebrospinal fluid by high-performance liquid chromatography with ultraviolet detection. J. Chromatogr. B Biomed. Sci. Appl.713(2),387–394 (1998).
    • 172  Huang CS, Boudinot FD, Feldman S. Radioimmunoassay for ziovudine in rat placenta and fetus. J. Pharm. Biomed. Anal.14(7),855–860 (1996).
    • 173  Yilmaz A, Gisslen M, Spudich S et al. Raltegravir cerebrospinal fluid concentrations in HIV-1 infection. PLoS ONE4(9),e6877 (2009).
    • 174  Clavel C, Peytavin G, Tubiana R et al. Raltegravir concentrations in the genital tract of HIV-1-infected women treated with a raltegravir-containing regimen (DIVA 01 study). Antimicrob. Agents Chemother.55(6),3018–3021 (2011).
    • 175  Calcagno A, Bonora S, D’avolio A et al. Raltegravir penetration in seminal plasma of healthy volunteers. Antimicrob. Agents Chemother.54(6),2744–2745 (2010).
    • 176  Calcagno A, Bonora S, Bertucci R, Lucchini A, D’avolio A, Di Perri G. Raltegravir penetration in the cerebrospinal fluid of HIV-positive patients. AIDS24(6),931–932 (2010).
    • 177  Keller MJ, Madan RP, Torres NM et al. A randomized trial to assess anti-HIV activity in female genital tract secretions and soluble mucosal immunity following application of 1% tenofovir gel. PLoS ONE6(1),e16475 (2011).
    • 178  Svensson JO, Sonnerborg A, Stahle L. Rapid and simple determination of indinavir in serum, urine, and cerebrospinal fluid using high-performance liquid chromatography. Ther. Drug Monit.22(5),626–629 (2000).
    • 179  Bernard L, Vuagnat A, Peytavin G et al. Relationship between levels of indinavir in hair and virologic response to highly active antiretroviral therapy. Ann. Intern. Med.137(8),656–659 (2002).
    • 180  Vernazza P, Daneel S, Schiffer V et al. The role of compartment penetration in PI-monotherapy: the Atazanavir-Ritonavir Monomaintenance (ATARITMO) trial. AIDS21(10),1309–1315 (2007).
    • 181  Hugen PW, Burger DM, De Graaff M et al. Saliva as a specimen for monitoring compliance but not for predicting plasma concentrations in patients with HIV treated with indinavir. Ther. Drug Monit.22(4),437–445 (2000).
    • 182  Anderson PL, Noormohamed SE, Henry K, Brundage RC, Balfour HH Jr., Fletcher CV. Semen and serum pharmacokinetics of zidovudine and zidovudine-glucuronide in men with HIV-1 infection. Pharmacotherapy20(8),917–922 (2000).
    • 183  Lowe SH, Van Leeuwen E, Droste JA et al. Semen quality and drug concentrations in seminal plasma of patients using a didanosine or didanosine plus tenofovir containing antiretroviral regimen. Ther. Drug Monit.29(5),566–570 (2007).
    • 184  Sparidans RW, Hoetelmans RM, Beijnen JH. Sensitive liquid chromatographic assay for amprenavir, a human immunodeficiency virus protease inhibitor, in human plasma, cerebrospinal fluid and semen. J. Chromatogr. B Biomed. Sci. Appl.742(1),185–192 (2000).
    • 185  Mueller BU, Lewis LL, Yuen GJ et al. Serum and cerebrospinal fluid pharmacokinetics of intravenous and oral lamivudine in human immunodeficiency virus-infected children. Antimicrob. Agents Chemother.42(12),3187–3192 (1998).
    • 186  Hamidi M. Simple and sensitive high-performance liquid chromatography method for the quantitation of indinavir in rat plasma and central nervous system. J. Sep. Sci.29(5),620–627 (2006).
    • 187  Lewis SR, White CA, Bartlett MG. Simultaneous determination of abacavir and zidovudine from rat tissues using HPLC with ultraviolet detection. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.850(1–2),45–52 (2007).
    • 188  Pereira AS, Kenney KB, Cohen MS et al. Simultaneous determination of lamivudine and zidovudine concentrations in human seminal plasma using high-performance liquid chromatography and tandem mass spectrometry. J. Chromatogr. B Biomed. Sci. Appl.742(1),173–183 (2000).
    • 189  Alnouti Y, White CA, Bartlett MG. Simultaneous determination of zidovudine and lamivudine from rat plasma, amniotic fluid and tissues by HPLC. Biomed. Chromatogr.18(9),641–647 (2004).
    • 190  Alnouti Y, Lewis SR, White CA, Bartlett MG. Simultaneous determination of zidovudine and lamivudine from rat tissues by liquid chromatography/tandem mass spectrometry. Rapid Commun. Mass Spectrom.19(4),503–508 (2005).
    • 191  Alnouti Y, White CA, Bartlett MG. Simultaneous quantitation of zidovudine and zidovudine monophosphate from plasma, amniotic fluid and tissues by micellar capillary electrophoresis. Biomed. Chromatogr.18(8),523–531 (2004).
    • 192  Brown KC, Patterson KB, Malone SA et al. Single and multiple dose pharmacokinetics of maraviroc in saliva, semen, and rectal tissue of healthy HIV-negative men. J. Infect. Dis.203(10),1484–1490 (2011).
    • 193  Haworth SJ, Christofalo B, Anderson RD, Dunkle LM. A single-dose study to assess the penetration of stavudine into human cerebrospinal fluid in adults. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol.17(3),235–238 (1998).
    • 194  Van Praag RM, Van Weert EC, Van Heeswijk RP et al. Stable concentrations of zidovudine, stavudine, lamivudine, abacavir, and nevirapine in serum and cerebrospinal fluid during 2 years of therapy. Antimicrob. Agents Chemother.46(3),896–899 (2002).
    • 195  Brady KA, Boston RC, Aldrich JL, Macgregor RR. Stavudine entry into cerebrospinal fluid after single and multiple doses in patients infected with human immunodeficiency virus. Pharmacotherapy25(1),10–17 (2005).
    • 196  Haas DW, Stone J, Clough LA et al. Steady-state pharmacokinetics of indinavir in cerebrospinal fluid and plasma among adults with human immunodeficiency virus type 1 infection. Clin. Pharmacol. Ther.68(4),367–374 (2000).
    • 197  Rezk NL, White N, Bridges AS et al. Studies on antiretroviral drug concentrations in breast milk: validation of a liquid chromatography–tandem mass spectrometric method for the determination of 7 anti-human immunodeficiency virus medications. Ther. Drug Monit.30(5),611–619 (2008).
    • 198  L’homme RF, Muro EP, Droste JA et al. Therapeutic drug monitoring of nevirapine in resource-limited settings. Clin. Infect. Dis.47(10),1339–1344 (2008).
    • 199  Van Lelyveld SF, Nijhuis M, Baatz F et al. Therapy failure following selection of enfuvirtide-resistant HIV-1 in cerebrospinal fluid. Clin. Infect. Dis.50(3),387–390 (2010).
    • 200  Pereira De Oliveira M, Garcion E, Venisse N, Benoit JP, Couet W, Olivier JC. Tissue distribution of indinavir administered as solid lipid nanocapsule formulation in mdr1a (+/+) and mdr1a (-/-) CF-1 mice. Pharm. Res.22(11),1898–1905 (2005).
    • 201  Else LJ, Lyons F, O’shea S et al. Total and unbound lopinavir concentrations in the female genital tract of HIV-1 infected women during pregnancy. AIDS25(5),722–725 (2011).
    • 202  Croteau D, Letendre S, Best BM et al. Total raltegravir concentrations in cerebrospinal fluid exceed the 50-percent inhibitory concentration for wild-type HIV-1. Antimicrob. Agents Chemother.54(12),5156–5160 (2010).
    • 203  Patterson TA, Binienda ZK, Newport GD et al. Transplacental pharmacokinetics and fetal distribution of 2’, 3’-didehydro-3’-deoxythymidine (d4T) and its metabolites in late-term rhesus macaques. Teratology62(2),93–99 (2000).
    • 204  Patterson TA, Binienda ZK, Lipe GW, Gillam MP, Slikker W Jr., Sandberg JA. Transplacental pharmacokinetics and fetal distribution of azidothymidine, its glucuronide, and phosphorylated metabolites in late-term rhesus macaques after maternal infusion. Drug Metab. Dispos.25(4),453–459 (1997).
    • 205  Pereira CM, Nosbisch C, Winter HR, Baughman WL, Unadkat JD. Transplacental pharmacokinetics of dideoxyinosine in pigtailed macaques. Antimicrob. Agents Chemother.38(4),781–786 (1994).
    • 206  Anderson BD, Hoesterey BL, Baker DC, Galinsky RE. Uptake kinetics of 2’,3’-dideoxyinosine into brain and cerebrospinal fluid of rats: intravenous infusion studies. J. Pharmacol. Exp. Ther.253(1),113–118 (1990).
    • 207  Vuong Le T, Ruckle JL, Blood AB et al. Use of accelerator mass spectrometry to measure the pharmacokinetics and peripheral blood mononuclear cell concentrations of zidovudine. J. Pharm. Sci.97(7),2833–2843 (2008).
    • 208  Akula SK, Rege AB, Dreisbach AW, Dejace PM, Lertora JJ. Valproic acid increases cerebrospinal fluid zidovudine levels in a patient with AIDS. Am. J. Med. Sci.313(4),244–246 (1997).
    • 209  Fox E, Bungay PM, Bacher J, Mccully CL, Dedrick RL, Balis FM. Zidovudine concentration in brain extracellular fluid measured by microdialysis: steady-state and transient results in rhesus monkey. J. Pharmacol. Exp. Ther.301(3),1003–1011 (2002).
    • 210  Odinecs A, Nosbisch C, Unadkat JD. Zidovudine does not affect transplacental transfer or systemic clearance of stavudine (2’,3’-didehydro-3’-deoxythymidine) in the pigtailed macaque (Macaca nemestrina). Antimicrob. Agents Chemother.40(6),1569–1571 (1996).
    • 211  Bennetto-Hood C, Bryson YJ, Stek A, King JR, Mirochnick M, Acosta EP. Zidovudine, lamivudine, and nelfinavir concentrations in amniotic fluid and maternal serum. HIV Clin. Trials10(1),41–47 (2009).
    • 212  Yeh RF, Rezk NL, Kashuba AD et al. Genital tract, cord blood, and amniotic fluid exposures of seven antiretroviral drugs during and after pregnancy in human immunodeficiency virus type 1-infected women. Antimicrob. Agents Chemother.53(6),2367–2374 (2009).
    • 213  Lowe SH, Wensing AM, Droste JA et al. No virological failure in semen during properly suppressive antiretroviral therapy despite subtherapeutic local drug concentrations. HIV Clin. Trials7(6),285–290 (2006).▪▪ Excellent review of male and female genital tract PKs with some method information.
    • 214  Else LJ, Taylor S, Back DJ, Khoo SH. Pharmacokinetics of antiretroviral drugs in anatomical sanctuary sites: the male and female genital tract. Antivir. Ther.16(8),1149–1167 (2011).
    • 215  Patterson KB, Prince HA, Kraft E et al. Penetration of tenofovir and emtricitabine in mucosal tissues: implications for prevention of HIV-1 transmission. Sci. Transl. Med.3(112),112re4 (2011).
    • 216  Schwartz JL, Rountree W, Kashuba AD et al. A multi-compartment, single and multiple dose pharmacokinetic study of the vaginal candidate microbicide 1% tenofovir gel. PLoS ONE6(10),e25974 (2011).
    • 217  Nuttall J, Kashuba A, Wang R et al. Pharmacokinetics of tenofovir following intravaginal and intrarectal administration of tenofovir gel to rhesus macaques. Antimicrob. Agents Chemother.56(1),103–109 (2012).
    • 218  Beigi R, Noguchi L, Parsons T et al. Pharmacokinetics and placental transfer of single-dose tenofovir 1% vaginal gel in term pregnancy. J. Infect. Dis.204(10),1527–1531 (2011).
    • 219  Dumond JB, Nicol MR, Kendrick RN et al. Pharmacokinetic modelling of efavirenz, atazanavir, lamivudine and tenofovir in the female genital tract of HIV-infected pre-menopausal women. Clin. Pharmacokinet.51(12),809–822 (2012).
    • 220  Anton PA, Cranston RD, Kashuba A et al. RMP-02/MTN-006: a phase 1 rectal safety, acceptability, pharmacokinetic, and pharmacodynamic study of tenofovir 1% gel compared with oral tenofovir disoproxil fumarate. AIDS Res. Hum. Retroviruses28(11),1412–1421 (2012).
    • 221  Tiraboschi JM, Niubo J, Ferrer E et al. Etravirine concentrations in seminal plasma in HIV-infected patients. J. Antimicrob. Chemother.68(1),184–187 (2013).
    • 222  Palombi L, Pirillo MF, Andreotti M et al. Antiretroviral prophylaxis for breastfeeding transmission in Malawi: drug concentrations, virological efficacy and safety. Antivir. Ther.17(8),1511–1519 (2012).
    • 223  Nirogi R, Bhyrapuneni G, Kandikere V et al. Pharmacokinetic profiling of efavirenz-emtricitabine-tenofovir fixed dose combination in pregnant and non-pregnant rats. Biopharm. Drug Dispos.33(5),265–277 (2012).
    • 224  Tiraboschi JM, Niubo J, Vila A, Perez-Pujol S, Podzamczer D. Etravirine concentrations in CSF in HIV-infected patients. J. Antimicrob. Chemother.67(6),1446–1448 (2012).
    • 225  Croteau D, Letendre S, Best BM et al. Therapeutic amprenavir concentrations in cerebrospinal fluid. Antimicrob. Agents Chemother.56(4),1985–1989 (2012).
    • 226  Moss JA, Baum MM, Malone AM et al. Tenofovir and tenofovir disoproxil fumarate pharmacokinetics from intravaginal rings. AIDS26(6),707–710 (2012).
    • 227  Clark MR, Johnson TJ, Mccabe RT et al. A hot-melt extruded intravaginal ring for the sustained delivery of the antiretroviral microbicide UC781. J. Pharm. Sci.101(2),576–587 (2012).
    • 228  Brown KC, Patterson KB, Jennings SH et al. Single- and multiple-dose pharmacokinetics of darunavir plus ritonavir and etravirine in semen and rectal tissue of HIV-negative men. J. Acquir. Immune Defic. Syndr.61(2),138–144 (2012).