Role of Drug Metabolic Enzymes and Transporters in Drug-Drug Interactions Between Antiretroviral and Antituberculosis Drugs

Abstract

Drug-drug interactions is one of the major determinant in drug development and clinical applications. Individual differences in pharmacokinetics may cause extensive variability in drug efficacy, toxicity and adverse drug reactions, and represent a major concern in drug development. According to world health organization, an estimated 1.2 million patients were diagnosed with HIV/TB coinfection in 2015, and approximately 400,000 coinfected individuals were died in 2016. During treatment of tuberculosis and human immunodeficiency virus (HIV) coinfections, a combination of multiple therapeutic drugs is used, which is potential for interactions between coadministered drugs. Drug metabolizing enzymes and transporters plays vital role in the disposition, pharmacokinetics as well as efficacy and toxicity of many antituberculosis (anti-TB) and antiretroviral (ARVs) drugs. The current understanding of drug-drug interactions involving the first-line antituberculosis and antiretroviral (ARVs) drugs are reviewed and summarized in this article emphasizing the role of drug transporters and metabolic enzymes. It is found that several clinical drug-interactions are caused by the phase I and II metabolic enzymes (cytochrome-P-450s, CYPs, UDP-glucuronosyltransferases, UGTs) and uptake/ efflux transporters, particularly permeability glycoprotein, brest cancer resistance protein, multidrug resistance protein and solute carrier transporters). Overall, this study will be helpful to understand the drug-interactions between the ARV or anti-TB drug regimen or with concomitantly used drugs at a glance. By understanding the unique functions and characteristics of enzymes and transporters, it may use in the management of drug interactions in the treatment of HIV and TB. Keywords: Drug-drug interactions, Metabolic Enzymes, Membrane Transporters, Antiretroviral and antituberculosis drugs