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

Abstract

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.

Pharmacogenetics as part of recommended precision medicine for tuberculosis treatment in African populations: Could it be a reality?

“…Together with INH, RIF forms the backbone of active and latent TB treatment. Considerable variation in RIF exposure is observed and explained by multiple genes, but no candidate gene has yet been identified for therapeutic drug monitoring of RIF 44 . A recent meta‐analysis by Sileshi et al 44 identified polymorphisms rs4149032 (g.38664C>T), rs2306283 (c.388A>G), and rs11045819 (c.463C>A) in the organic anion transporting polypeptide 1B1 (OATP1B1) gene ( SLCO1B1 ) to be of importance.…”

“…Considerable variation in RIF exposure is observed and explained by multiple genes, but no candidate gene has yet been identified for therapeutic drug monitoring of RIF 44 . A recent meta‐analysis by Sileshi et al 44 identified polymorphisms rs4149032 (g.38664C>T), rs2306283 (c.388A>G), and rs11045819 (c.463C>A) in the organic anion transporting polypeptide 1B1 (OATP1B1) gene ( SLCO1B1 ) to be of importance. These variants have repeatedly been associated with RIF plasma concentrations and susceptibility to anti‐TB drug‐induced liver injury (ATDILI), 45 including in African populations 26,46 .…”

“…African populations are further categorized into geographical regions, North ("N"), Central ("C"), East ("E"), West ("W"), and South ("S"). and constitutive androstane receptor (CAR), metabolizing enzymes cholinesterase enzyme 1 (CES1), and arylacetamide deacetylase (AADAC), are still inconclusive, 44 with reports often describing associations only in specific populations. [47][48][49] For example, only one study described an effect of ABCB1 3435C>T on RIF plasma concentration in Mexican patients 50 and only one study found an association of increased RIF plasma concentrations and CES2 c.-22263A>G (g.738A>G) in Korean patients.…”

“…These variants have repeatedly been associated with RIF plasma concentrations and susceptibility to anti‐TB drug‐induced liver injury (ATDILI), 45 including in African populations. 26 , 46 Association studies with RIF pharmacokinetics and anion transporting polypeptides P‐glycoprotein ( ABCB1 or MDR1 gene), pregnane X receptor, and constitutive androstane receptor ( CAR ), metabolizing enzymes cholinesterase enzyme 1 ( CES1 ), and arylacetamide deacetylase ( AADAC ), are still inconclusive, 44 with reports often describing associations only in specific populations. 47 , 48 , 49 For example, only one study described an effect of ABCB1 3435C>T on RIF plasma concentration in Mexican patients 50 and only one study found an association of increased RIF plasma concentrations and CES2 c.‐22263A>G (g.738A>G) in Korean patients.…”