Genetic Diversity in Drug Transporters: Impact in African Populations

Rajman, Iris; Knapp, Laura; Hanna, Imad

doi:10.1111/cts.12769

Cited by 16 publications

(11 citation statements)

References 64 publications

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“…rs4149032 is an intronic SNP most common in the African population. 48 , 49 Gengiah et al reported high frequency in the SLCO1B1 (rs4149032) gene polymorphism and its association with low median rifampicin C2.5hr in the heterozygous and homozygous variant carriers. 32 Similarly, Chigutsa et al reported high allelic frequency of the SLCO1B1 rs4149032 polymorphism and 28% reductions in the bioavailability of rifampin for homozygous variants.…”

Section: Resultsmentioning

confidence: 99%

Effect of Genetic Variations in Drug-Metabolizing Enzymes and Drug Transporters on the Pharmacokinetics of Rifamycins: A Systematic Review

Sileshi¹,

Tefera²,

Makonnen³

et al. 2022

PGPM

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Background Rifamycins are a novel class of antibiotics clinically approved for tuberculosis chemotherapy. They are characterized by high inter-individual variation in pharmacokinetics. This systematic review aims to present the contribution of genetic variations in drug-metabolizing enzymes and transporter proteins to the inter-individual variation of rifamycin pharmacokinetics. Method We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. The search for relevant studies was done through PubMed, Embase, Web of Science, and Scopus databases. Studies reporting single nucleotide polymorphism in drug transporters and metabolizing enzymes’ influence on rifamycin pharmacokinetics were solely included. Two reviewers independently performed data extraction. Results The search identified 117 articles of which 15 fulfilled the eligibility criteria and were included in the final data synthesis. The single nucleotides polymorphism in the drug transporters SLCO1B1 rs4149032, rs2306283, rs11045819, and ABCB1 rs1045642 for rifampicin, drug metabolizing enzyme AADAC rs1803155 for rifapentine and CES2 c.-22263A>G (g.738A>G) for rifampicin partly contributes to the variability of pharmacokinetic parameters in tuberculosis patients. Conclusion The pharmacokinetics of rifamycins is influenced by genetic variation of drug-metabolizing enzymes and transporters. Controlled clinical studies are, however, required to establish these relationships.

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Section: Resultsmentioning

confidence: 99%

Effect of Genetic Variations in Drug-Metabolizing Enzymes and Drug Transporters on the Pharmacokinetics of Rifamycins: A Systematic Review

Sileshi¹,

Tefera²,

Makonnen³

et al. 2022

PGPM

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“…Together these studies could be used to adjust the standard recommended dose of ARV and TB drug for the African population that accounts for the presence of SNPs (Dandara et al, 2011;Rajman et al, 2020). The effects of SNPs on drug transporter genes have also been associated with increased plasma concentrations of TFV.…”

Section: Genetic Polymorphismsmentioning

confidence: 99%

“…Pharmacogenetic studies conducted with African populations have also shown high genetic diversity, which subsequently leads to varied drug transporter function and expression levels; impacting drug pharmacokinetics differently as reviewed by Rajman et al (2020) . The presence of the SLCO1B1 SNP 463C/A rs11045819 encoding the OATP1B1 protein was shown to impact rifampin pharmacokinetics differently in African populations ( Weiner et al, 2010 ; Dompreh et al, 2018 ).…”

Section: Biological Factors Modulating Drug Transporter Expression An...mentioning

confidence: 99%

Pharmacogenomics of drug transporters for antiretroviral long-acting pre-exposure prophylaxis for HIV

et al. 2022

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The use of antiretrovirals (ARVs) as oral, topical, or long-acting pre-exposure prophylaxis (PrEP) has emerged as a promising strategy for HIV prevention. Clinical trials testing Truvada® [tenofovir disoproxil fumarate (TDF)/tenofovir (TFV) and emtricitabine (FTC)] as oral or topical PrEP in African women showed mixed results in preventing HIV infections. Since oral and topical PrEP effectiveness is dependent on adequate drug delivery and availability to sites of HIV infection such as the blood and female genital tract (FGT); host biological factors such as drug transporters have been implicated as key regulators of PrEP. Drug transporter expression levels and function have been identified as critical determinants of PrEP efficacy by regulating PrEP pharmacokinetics across various cells and tissues of the blood, renal tissues, FGT mucosal tissues and other immune cells targeted by HIV. In addition, biological factors such as genetic polymorphisms and genital inflammation also influence drug transporter expression levels and functionality. In this review, drug transporters and biological factors modulating drug transporter disposition are used to explain discrepancies observed in PrEP clinical trials. This review also provides insight at a pharmacological level of how these factors further increase the susceptibility of the FGT to HIV infections, subsequently contributing to ineffective PrEP interventions in African women.

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“…In humans, several factors account for inter- and intra-individual differences in oral bioavailability. These include, but are not restricted to: GI surgery or chronic inflammatory intestinal conditions [ 36 ], co-administration of drugs [ 37 ], food–drug interactions, feeding condition, age and sex [ 38 ] of the patient, ethnic background [ 39 ] and the patient’s unique physiology (including phenotypic polymorphisms) [ 40 ] ( Figure 1 ). In particular, polymorphisms in transporter genes affecting expression or activity can influence bioavailability of drugs and toxins and may also predispose to certain diseases [ 2 ].…”

Section: Bioavailability and The Intestinal Epitheliummentioning

confidence: 99%

Drug Screening, Oral Bioavailability and Regulatory Aspects: A Need for Human Organoids

Zietek

Boomgaarden²,

Rath

2021

Pharmaceutics

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The intestinal epithelium critically contributes to oral bioavailability of drugs by constituting an important site for drug absorption and metabolism. In particular, intestinal epithelial cells (IEC) actively serve as gatekeepers of drug and nutrient availability. IECs’ transport processes and metabolism are interrelated to the whole-body metabolic state and represent potential points of origin as well as therapeutic targets for a variety of diseases. Human intestinal organoids represent a superior model of the intestinal epithelium, overcoming limitations of currently used in vitro models. Caco2 cells or rodent explant models face drawbacks such as their cancer and non-human origin, respectively, but are commonly used to study intestinal nutrient absorption, enterocyte metabolism and oral drug bioavailability, despite poorly correlative data. In contrast, intestinal organoids allow investigating distinct aspects of bioavailability including spatial resolution of transport, inter-individual differences and high-throughput screenings. As several countries have already developed strategic roadmaps to phase out animal experiments for regulatory purposes, intestinal organoid culture and organ-on-a-chip technology in combination with in silico approaches are roads to go in the preclinical and regulatory setup and will aid implementing the 3Rs (reduction, refinement and replacement) principle in basic science.

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Genetic Diversity in Drug Transporters: Impact in African Populations

Cited by 16 publications

References 64 publications

Effect of Genetic Variations in Drug-Metabolizing Enzymes and Drug Transporters on the Pharmacokinetics of Rifamycins: A Systematic Review

Effect of Genetic Variations in Drug-Metabolizing Enzymes and Drug Transporters on the Pharmacokinetics of Rifamycins: A Systematic Review

Pharmacogenomics of drug transporters for antiretroviral long-acting pre-exposure prophylaxis for HIV

Drug Screening, Oral Bioavailability and Regulatory Aspects: A Need for Human Organoids

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