Semen and Serum Pharmacokinetics of Zidovudine and Zidovudine‐Glucuronide in Men with HIV‐1 Infection

Anderson, Peter L.; Noormohamed, Saleem E.; Henry, Keith; Brundage, Richard C.; Balfour, Henry H.; Fletcher, Courtney V.

doi:10.1592/phco.20.11.917.35263

Cited by 24 publications

(23 citation statements)

References 37 publications

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“…Examples of such drugs include many antiretroviral medications used to treat infection of human immunodeficiency virus (HIV). By limiting the entry of many antiretrovirals into the seminiferous tubules, the BTB may be contributing to the testes' serving as a sanctuary site for HIV (Byrn and Kiessling, 1998;Anderson et al, 2000;Olson, 2002;Dahl et al, 2010;Avery et al, 2011). Because the tight junctions of the BTB prevent or reduce paracellular diffusion of hydrophilic drugs, transcellular transport through the Sertoli cells is required for antiretrovirals to bypass the BTB.…”

Section: Introductionmentioning

confidence: 99%

Localization of Multidrug Resistance-Associated Proteins along the Blood-Testis Barrier in Rat, Macaque, and Human Testis

2013

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The blood-testis barrier (BTB) prevents the entry of many drugs into seminiferous tubules, which can be beneficial for therapy not intended for the testis but may decrease drug efficacy for medications requiring entry to the testis. Previous data have shown that some of the transporters in the multidrug resistance-associated protein (MRP) family (ABCC) are expressed in the testis. By determining the subcellular localization of these transporters, their physiologic function and effect on drug disposition may be better predicted. Using immunohistochemistry (IHC), we determined the site of expression of the MRP transporters expressed in the testis, namely, MRP1, MRP4, MRP5, and MRP8, from immature and mature rats, rhesus macaques, and adult humans. We determined that in all species MRP1 was restricted to the basolateral membrane of Sertoli cells, MRP5 is located in Leydig cells, and MRP8 is located in round spermatids, whereas MRP4 showed speciesspecific localization. MRP4 is expressed on the basolateral membrane of Sertoli cells in human and nonhuman primates, but on the apical membrane of Sertoli cells in immature and mature rats, representing a potential caution when using rat models as a means for studying drug disposition across the BTB. These data suggest that MRP1 may limit drug disposition into seminiferous tubules, as may MRP4 in human and nonhuman primates but not in rats. These data also suggest that MRP5 and MRP8 may not have a major impact on the penetration of drugs across the BTB.

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Section: Introductionmentioning

confidence: 99%

Localization of Multidrug Resistance-Associated Proteins along the Blood-Testis Barrier in Rat, Macaque, and Human Testis

2013

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“…Our work suggests that these basic cellular processes differ in ways that result in different PK profiles in SMCs for nucleoside reverse transcriptase inhibitors and that each agent with clinical relevance must be studied to elucidate individual mechanisms. Differences in cellular activation state (17), the specific cell populations that comprise the mononuclear cell pool in semen and blood (18), drug metabolism (i.e., ZDV glucuronidation) (19), and kinase activities (16) may contribute to these differences. For both PBMCs and SMCs, the catabolic process for the triphosphate metabolites is not well described, although previous modeling work combining ex vivo and in vivo studies of 3TC-TP in PBMCs suggests that catabolism of 3TC-TP in PBMCs is less likely to be a critical determinant of disposition and more likely to be dependent on the total 3TC parent and metabolite pools within the cell (20).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Modeling of Lamivudine and Zidovudine Triphosphates Predicts Differential Pharmacokinetics in Seminal Mononuclear Cells and Peripheral Blood Mononuclear Cells

Dumond¹,

Yang²,

Kendrick³

et al. 2015

Antimicrob Agents Chemother

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The male genital tract is a potential site of viral persistence. Therefore, adequate concentrations of antiretrovirals are required to eliminate HIV replication in the genital tract. Despite higher zidovudine (ZDV) and lamivudine (3TC) concentrations in seminal plasma (SP) than in blood plasma (BP) (SP/BP drug concentration ratios of 2.3 and 6.7, respectively), we have previously reported lower relative intracellular concentrations of their active metabolites, zidovudine triphosphate (ZDV-TP) and lamivudine triphosphate (3TC-TP), in seminal mononuclear cells (SMCs) than in peripheral blood mononuclear cells (PBMCs) (SMC/ PBMC drug concentration ratios of 0.36 and 1.0, respectively). Here, we use population pharmacokinetic (PK) modeling-based methods to simultaneously describe parent and intracellular metabolite PK in blood, semen, and PBMCs and SMCs. From this model, the time to steady state in each matrix was estimated, and the results indicate that the PK of 3TC-TP and ZDV-TP in PBMCs are different from the PK of the two in SMCs and different for the two triphosphates. We found that steady-state conditions in PBMCs were achieved within 2 days for ZDV-TP and 3 days for 3TC-TP. However, steady-state conditions in SMCs were achieved within 2 days for ZDV-TP and 2 weeks for 3TC-TP. Despite this, or perhaps because of it, ZDV-TP in SMCs does not achieve the surrogate 50% inhibitory concentration (IC 50 ) (as established for PBMCs, assuming SMC IC 50 ‫؍‬ PBMC IC 50 ) at the standard 300-mg twice-daily dosing. Mechanistic studies are needed to understand these differences and to explore intracellular metabolite behavior in SMCs for other nucleoside analogues used in HIV prevention, treatment, and cure.O ngoing viral replication in the male genital tract poses challenges for HIV prevention, treatment, and cure. From a prevention standpoint, virus in semen remains a major vector of HIV transmission; in serodiscordant heterosexual couples, early initiation of antiretroviral (ARV) treatment in the infected partner, with maintained suppression of peripheral HIV RNA, can reduce the rate of transmission by 96%, compared to delaying ARV treatment until later in the course of disease (1). The single linked HIV transmission event in the HPTN052 early treatment arm was from an infected male to his uninfected female partner within approximately 29 days of starting ARV therapy (1, 2). Additionally, to date, evidence strongly suggests that early, effective antiretroviral treatment limits the size of the viral reservoir, providing the best chance of HIV eradication (3). Finally, ongoing viral replication has been demonstrated in sanctuary sites, such as the central nervous system, gut-associated lymphoid tissue, and the genital tract, where antiretroviral concentrations may differ from those seen systemically (reviewed in reference 4). Since HIV eradication will not be possible with ongoing viral replication in sanctuary compartments, it is important to select ARVs with optimized pharmacokinetic (PK) and pharmacodynamic profiles to...

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“…55 ZDV also penetrates into semen and cervicovaginal fluid nearly 2 to 3 fold more in these compartments in comparison with plasma; again the ratio changes significantly over the dose interval as above. 56,57 This may be an important pharmacologic consideration for designing pre-or post exposure prophylaxis regimens in the future. ZDV is known to cross the placenta in pregnancy and penetrates breast milk, but breast milk concentrations are not high enough to elicit measurable concentrations in the feeding infant.…”

Section: Clinical Pharmacokineticsmentioning

confidence: 99%

Zidovudine and Lamivudine for HIV Infection

Anderson

Rower²

2010

Clinical Medicine Reviews in Therapeutics

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Zidovudine and lamivudine (ZDV and 3TC) are long-standing nucleoside analog-reverse transcriptase inhibitors (NRTIs) with extensive clinical experience in a wide spectrum of patients from in utero through childhood and adult ages. The safety profiles of both drugs are well-known and side effects for ZDV most commonly include nausea/vomiting, fatigue, anemia/neutopenia, and lipoatrophy; while 3TC is well-tolerated. ZDV-3TC is currently a viable alternative NRTI backbone for initial three-drug therapy of HIV infection when tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) cannot be used because of a relative or absolute contraindication. ZDV-3TC continue to be viable alternatives for children, pregnant women and in resource limited settings where other recommended options are not readily available. ZDV-3TC penetrate the Central Nervous System (CNS) well, which makes ZDV-3TC attractive for use in patients with HIV-associated neurological deficits. Additional benefits of these drugs may include the use of ZDV in combination with certain NRTIs to exert selective pressure to prevent particular drug resistance mutations from developing, and giving a short course of ZDV-3TC to prevent resistance after prophylactic single dose nevirapine.

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Semen and Serum Pharmacokinetics of Zidovudine and Zidovudine‐Glucuronide in Men with HIV‐1 Infection

Abstract: Zidovudine and zidovudine-glucuronide reach high levels in seminal plasma relative to serum. The virologic, pharmacodynamic, and public health implications of distribution to this compartment require further study.

Cited by 24 publications

References 37 publications

Localization of Multidrug Resistance-Associated Proteins along the Blood-Testis Barrier in Rat, Macaque, and Human Testis

Localization of Multidrug Resistance-Associated Proteins along the Blood-Testis Barrier in Rat, Macaque, and Human Testis

Pharmacokinetic Modeling of Lamivudine and Zidovudine Triphosphates Predicts Differential Pharmacokinetics in Seminal Mononuclear Cells and Peripheral Blood Mononuclear Cells

Zidovudine and Lamivudine for HIV Infection

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