Multimodal analysis of drug transporter expression in gastrointestinal tissue

Thompson, Corbin G.; Fallon, John K.; Mathews, Michelle; Charlins, Paige; Remling‐Mulder, Leila; Kovářová, Martina; Adamson, Lourdes; Srinivas, Nithya; Schauer, Amanda P.; Sykes, Craig; Luciw, Paul A.; García, J. Víctor; Akkina, Ramesh; Smith, Philip C.; Kashuba, Angela D. M.

doi:10.1097/qad.0000000000001554

Cited by 11 publications

(21 citation statements)

References 33 publications

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“…First, the quantitative relationship between transporter function and messenger RNA (mRNA) levels is not well understood. Levels of mRNA are highly variable and poorly correlated with protein expression [7,8] and/or function of transporters [9]. Recent reports elucidated the role of microRNAs, short noncoding RNAs, which inhibit the translation of mRNA into proteins.…”

Section: Effect Of P-gp Inducers On P-gp Substratesmentioning

confidence: 99%

Effect of P-glycoprotein (P-gp) Inducers on Exposure of P-gp Substrates: Review of Clinical Drug–Drug Interaction Studies

et al. 2020

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Understanding transporter-mediated drug-drug interactions (DDIs) for investigational agents is important during drug development to assess DDI liability, its clinical relevance, and to determine appropriate DDI management strategies. P-glycoprotein (P-gp) is an efflux transporter that influences the pharmacokinetics (PK) of various compounds. Assessing transporter induction in vitro is challenging and is not always predictive of in vivo effects, and hence there is a need to consider clinical DDI studies; however, there is no clear guidance on when clinical evaluation of transporter induction is required. Furthermore, there is no proposed list of index transporter inducers to be used in clinical studies. This review evaluated DDI studies with known P-gp inducers to better understand the mechanism and site of P-gp induction, as well as the magnitude of induction effect on the exposure of P-gp substrates. Our review indicates that P-gp and cytochrome P450 (CYP450) enzymes are coregulated via the pregnane xenobiotic receptor (PXR) and the constitutive androstane receptor (CAR). The magnitude of the decrease in substrate drug exposure by P-gp induction is generally less than that of CYP3A. Most P-gp inducers reduced total bioavailability with a minor impact on renal clearance, despite known expression of P-gp at the apical membrane of the kidney proximal tubules. Rifampin is the most potent P-gp inducer, resulting in an average reduction in substrate exposure ranging between 20 and 67%. For other inducers, the reduction in P-gp substrate exposure ranged from 12 to 42%. A lower reduction in exposure of the P-gp substrate was observed with a lower dose of the inducer and/or if the administration of the inducer and substrate was simultaneous, i.e. not staggered. These findings suggest that clinical evaluation of the impact of P-gp inducers on the PK of investigational agents that are substrates for P-gp might be warranted only for compounds with a relatively steep exposure-efficacy relationship.

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Section: Effect Of P-gp Inducers On P-gp Substratesmentioning

confidence: 99%

Effect of P-glycoprotein (P-gp) Inducers on Exposure of P-gp Substrates: Review of Clinical Drug–Drug Interaction Studies

et al. 2020

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“…Methodology related to the infection, dosing, and tissue collection with subsequent ARV plasma and tissue quantification analyses via LC-MS/MS are described previously (19,20,31,65) and are located in the supplemental material. Demographic data for human tissue samples are described in Table S1 in the supplemental material.…”

Section: Animal Infection Dosing and Tissue Collection And Arv Plasmentioning

confidence: 99%

“…Previously identified factors that affect drug distribution into HIV reservoirs include sex, drug transporters, and species differences (16)(17)(18). Our group has also characterized drug transporter expression in GALT and lymph nodes (19,20). In this study, we aim to quantify ARV concentrations and to evaluate these factors affecting ARV distribution in splenic tissues across three commonly used preclinical species-two humanized mouse models and an NHP model (21,22)-and humans.…”

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confidence: 99%

Antiretroviral Penetration and Drug Transporter Concentrations in the Spleens of Three Preclinical Animal Models and Humans

Devanathan

Fallon

White

et al. 2020

Antimicrob Agents Chemother

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Adequate antiretroviral (ARV) concentrations in lymphoid tissues are critical for optimal antiretroviral therapy. While the spleen contains 25% of the body's lymphocytes, there are minimal data on ARV penetration in this organ. This study quantified total and protein-unbound splenic ARV concentrations, and determine whether drug transporters, sex, or infection status were modifiers of these concentrations in animal models and humans. Two humanized mice models [hu-HSC-Rag (n=36; 18 HIV+ and 18 HIV-); bone marrow-liver-thymus (n=13; 7 HIV+ and 6 HIV-)] and one nonhuman primate model [NHP; rhesus macaque (n=18; 10 SHIV+ and 8 SHIV-) were dosed to steady-state with ARV combinations. HIV+ human spleens (N=14) from National NeuroAIDS Tissue Consortium were analyzed post-mortem (up to 24h post-dose). ARV concentrations were measured by LC-MS/MS, drug transporter concentrations were measured with LC-MS proteomics, and protein binding in NHP spleens was determined by rapid equilibrium dialysis. Mice generally had the lowest splenic concentrations of the three species. Protein binding in splenic tissue was 6-96%, compared to 76-99% in blood plasma. NHPs had quantifiable Mrp4, Bcrp, and Ent1 concentrations, and humans had quantifiable ENT1 concentrations. None significantly correlated with tissue ARV concentrations. There was also no observable influence of infection status or sex. With these dosing strategies, NHP splenic penetration most closely resembled humans. These data can inform tissue pharmacokinetic scaling to humans to target HIV reservoirs by identifying important species related differences.

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“…In order to determine the free fraction of MVC in the mucosal tissues, the protein binding of MVC was determined by rapid equilibrium dialysis in the lower FGT and colorectal tissue of six male and three female adult rhesus macaques. Details of this animal study have been described previously (31). In brief, six male and three female adult rhesus macaques were dosed to steady-state with TFV, FTC, MVC, and RAL.…”

Section: Methodsmentioning

confidence: 99%

Translational Approach to Predicting the Efficacy of Maraviroc-Based Regimens as HIV Preexposure Prophylaxis

Srinivas

Cottrell

Maffuid

et al. 2020

Antimicrob Agents Chemother

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Maraviroc-based regimens have been explored as preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV). In this study, we utilized mucosal tissue drug exposure data, combined with target concentrations generated in vitro, in a pharmacokinetic-pharmacodynamic analysis to predict the effects of drug combinations and adherence on PrEP efficacy. Mucosal tissue concentrations of maraviroc were measured in 24 healthy women. The 90% effective concentrations (EC90) of maraviroc (alone and combined with tenofovir and emtricitabine) for protection against HIV were identified in CD4+ T cells. Monte Carlo simulations were performed to identify dosing strategies to protect colorectal and female genital tract (FGT) tissues from HIV infection. Colorectal maraviroc concentrations were 350-fold higher than in the FGT. Under steady-state conditions, our model predicted that one 300-mg dose/week was sufficient to protect colorectal tissue from HIV in 99% of the population, while 300 mg daily would protect the FGT in only 63% of the population. FGT protection increased to >90% when maraviroc was used in combination with tenofovir (5 doses/week) or emtricitabine (3 doses/week). Poor adherence resulted in a drastic decrease in efficacy in the FGT but not colorectal tissue. However, greater forgiveness was seen when maraviroc was combined with tenofovir or emtricitabine, suggesting that maraviroc should not be used alone as PrEP.

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Multimodal analysis of drug transporter expression in gastrointestinal tissue

Cited by 11 publications

References 33 publications

Effect of P-glycoprotein (P-gp) Inducers on Exposure of P-gp Substrates: Review of Clinical Drug–Drug Interaction Studies

Effect of P-glycoprotein (P-gp) Inducers on Exposure of P-gp Substrates: Review of Clinical Drug–Drug Interaction Studies

Antiretroviral Penetration and Drug Transporter Concentrations in the Spleens of Three Preclinical Animal Models and Humans

Translational Approach to Predicting the Efficacy of Maraviroc-Based Regimens as HIV Preexposure Prophylaxis

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