Drug uptake transporters in antiretroviral therapy

Minuesa, Gerard; Huber-Ruano, Isabel; Pastor‐Anglada, Marçal; Koepsell, Hermann; Clotet, Bonaventura; Martínez-Picado, Javier

doi:10.1016/j.pharmthera.2011.06.007

Cited by 65 publications

(57 citation statements)

References 117 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HIV/AIDS patients display lower relative bioavailability of efavirenz than healthy subjects, and hence direct extrapolation of efavirenz exposure data from healthy volunteers to the target patient population may not be applicable (8). Moreover, since most antiretroviral drugs, including efavirenz, exert their therapeutic effects in the target immune cells (15), characterization of the intracellular time course of these drugs may result in the design of a more accurate and reliable dosage regimen. We are aware of no PK models that describe the time course of either EFV or 8OHEFV in plasma and intracellular compartments simultaneously.…”

mentioning

confidence: 99%

Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients

Habtewold

Aklillu

Makonnen

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The objectives of this study were to characterize the population pharmacokinetics (PK) of efavirenz (EFV) and 8-hydroxy-efavirenz (8OHEFV) in plasma and peripheral blood mononuclear cells (PBMCs) and to explore covariates affecting the PK parameters. Fifty-one patients had steady-state 0-to-24-h concentrations of EFV and 8OHEFV in plasma with corresponding concentrations in PBMCs, while 261 patients had one or two sparse concentrations at 16 Ϯ 1 h postdose at weeks 4 and/or 16. The pharmacogenetic markers CYP2B6*6, CYP3A5*3, CYP3A5*6, UGT2B7*2, ABCB1 (3435C¡T, 3842A¡G), OATP1B1*1B, and OATP1B1*5, the presence of a rifampin-based antituberculosis (anti-TB) regimen, baseline body weight and organ function values, and demographic factors were explored as covariates. EFV concentration data were well described by a two-compartment model with first-order absorption (K a ) and absorption lag time (A lag ) (K a ϭ 0.2 h Ϫ1 ; A lag ϭ 0.83 h; central compartment clearance [CL c /F] for CYP2B6*1/*1 ϭ 18 liters/h, for CYP2B6*1/*6 ϭ 14 liters/h, and for CYP2B6*6/*6 ϭ 8.6 liters/h) and PBMCs as a peripheral compartment. EFV transfer from plasma to PBMCs was first order (CL p /F ϭ 32 liters/h), followed by capacity-limited return (V max ϭ 4,400 ng/ml/h; K m ϭ 710 ng/ml). Similarly, 8OHEFV displayed a first-order elimination and distribution to PBMCs, with a capacity-limited return to plasma. No covariate relationships resulted in a significant explanation of interindividual variability (IIV) on the estimated PK parameters of EFV and 8OHEFV, except for CYP2B6*6 genotypes, which were consistent with prior evidence. Both EFV and 8OHEFV accumulated to higher concentrations in PBMCs than in plasma and were well described by first-order input and Michaelis-Menten kinetics removal from PBMCs. CYP2B6*6 genotype polymorphisms were associated with decreased EFV and 8OHEFV clearance.KEYWORDS efavirenz, 8-hydroxy-efavirenz, peripheral blood mononuclear cells, population pharmacokinetics E favirenz (EFV)-based antiretroviral therapy remains the preferred first-line treatment option in important international guidelines, including those of the World Health Organization (1). EFV displays a wide between-patient pharmacokinetic (PK) variability (2, 3). This is ascribed partially to genetic variation of the CYP2B6 enzyme, which is primarily responsible for the metabolism of efavirenz to 8-hydroxy-efavirenz (8OHEFV) (4, 5). Efavirenz is described to have a narrow safety margin (6-8). In addition, a couple

show abstract

mentioning

confidence: 99%

Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients

Habtewold

Aklillu

Makonnen

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…3 In this context, it was proposed that one of the goals of future clinical trials should be to attain the highest tolerable drug concentration in the vagina. 3,7 Since most microbicide candidates are substrates of transporters and/or metabolizing enzymes, [8][9][10] there is growing interest in understanding the role of transporters and enzymes in controlling the level of drug present in the cells in the lower genital tract. Transporters residing on the cell membrane can efflux or uptake drug molecules, controlling the extent of drug entry into the cell.…”

mentioning

confidence: 99%

Short Communication: Expression of Transporters and Metabolizing Enzymes in the Female Lower Genital Tract: Implications for Microbicide Research

Zhou

Cost

et al. 2013

AIDS Research and Human Retroviruses

View full text Add to dashboard Cite

Topical vaginal microbicides have been considered a promising option for preventing the male-to-female sexual transmission of HIV; however, clinical trials to date have not clearly demonstrated robust and reproducible effectiveness results. While multiple approaches may help enhance product effectiveness observed in clinical trials, increasing the drug exposure in lower genital tract tissues is a compelling option, given the difficulty in achieving sufficient drug exposure and positive correlation between tissue exposure and microbicide efficacy. Since many microbicide drug candidates are substrates of transporters and/or metabolizing enzymes, there is emerging interest in improving microbicide exposure and efficacy through local modulation of transporters and enzymes in the female lower genital tract. However, no systematic information on transporter/enzyme expression is available for ectocervical and vaginal tissues of premenopausal women, the genital sites most relevant to microbicide drug delivery. The current study utilized reverse transcriptase polymerase chain reaction (RT-PCR) to examine the mRNA expression profile of 22 transporters and 19 metabolizing enzymes in premenopausal normal human ectocervix and vagina. Efflux and uptake transporters important for antiretroviral drugs, such as P-gp, BCRP, OCT2, and ENT1, were found to be moderately or highly expressed in the lower genital tract as compared to liver. Among the metabolizing enzymes examined, most CYP isoforms were not detected while a number of UGTs such as UGT1A1 were highly expressed. Moderate to high expression of select transporters and enzymes was also observed in mouse cervix and vagina. The implications of this information on microbicide research is also discussed, including microbicide pharmacokinetics, the utilization of the mouse model in microbicide screening, as well as the in vivo functional studies of cervicovaginal transporters and enzymes.

show abstract

“…Integrase inhibitors (e.g., elvitegravir, dolutegravir), protease inhibitors (e.g., saquinavir, ritonavir), and nonnucleoside reverse transcriptase inhibitors (e.g., zidovudine) are anti-HIV agents known to interact with some transporters and induce transportermediated drug interactions (20,21,(33)(34)(35). Delamanid may be used concomitantly with these agents for the treatment of TB in patients coinfected with HIV.…”

Section: Discussionmentioning

confidence: 99%

“…Erythromycin can inhibit the function of P-gp, resulting in an increased absorption of fexofenadine, in addition to its effects on CYP3A (19). Antiretroviral agents that may be used to treat HIV coinfection can also influence the pharmacokinetics and clinical effects of other drugs (20,21,40). Therefore, there is an urgent need for a careful in vitro characterization of these potential DDIs and, if warranted, assessment of the possible clinical consequences of these DDIs.…”

mentioning

confidence: 99%

Antitubercular Agent Delamanid and Metabolites as Substrates and Inhibitors of ABC and Solute Carrier Transporters

Sasabe

Shimokawa

Shibata

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

b Delamanid (Deltyba, OPC-67683) is the first approved drug in a novel class of nitro-dihydro-imidazooxazoles developed for the treatment of multidrug-resistant tuberculosis. Patients with tuberculosis require treatment with multiple drugs, several of which have known drug-drug interactions. Transporters regulate drug absorption, distribution, and excretion; therefore, the inhibition of transport by one agent may alter the pharmacokinetics of another, leading to unexpected adverse events. Therefore, it is important to understand how delamanid affects transport activity. In the present study, the potencies of delamanid and its main metabolites as the substrates and inhibitors of various transporters were evaluated in vitro. Delamanid was not transported by the efflux ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp; MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), solute carrier (SLC) transporters, organic anion-transporting polypeptides, or organic cation transporter 1. Similarly, metabolite 1 (M1) was not a substrate for any of these transporters except P-gp. Delamanid showed no inhibitory effect on ABC transporters MDR1, BCRP, and bile salt export pump (BSEP; ABCB11), SLC transporters, or organic anion transporters. M1 and M2 inhibited P-gp-and BCRP-mediated transport but did so only at the 50% inhibitory concentrations (M1, 4.65 and 5.71 mol/liter, respectively; M2, 7.80 and 6.02 mol/liter, respectively), well above the corresponding maximum concentration in plasma values observed following the administration of multiple doses in clinical trials. M3 and M4 did not affect the activities of any of the transporters tested. These in vitro data suggest that delamanid is unlikely to have clinically relevant interactions with drugs for which absorption and disposition are mediated by this group of transporters.

show abstract

Drug uptake transporters in antiretroviral therapy

Cited by 65 publications

References 117 publications

Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients

Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients

Short Communication: Expression of Transporters and Metabolizing Enzymes in the Female Lower Genital Tract: Implications for Microbicide Research

Antitubercular Agent Delamanid and Metabolites as Substrates and Inhibitors of ABC and Solute Carrier Transporters

Contact Info

Product

Resources

About