Comparative study of the effects of antituberculosis drugs and antiretroviral drugs on cytochrome P450 3A4 and P-glycoprotein

Abstract

Predicting drug-drug interactions (DDIs) related to cytochrome P450 (CYP), such as CYP3A4 and one of the major drug transporters, P-glycoprotein (P-gp), is crucial in the development of future chemotherapeutic regimens to treat tuberculosis (TB) and TB/AIDS coinfection cases. We evaluated the effects of 30 anti-TB drugs, novel candidates, macrolides, and representative antiretroviral drugs on human CYP3A4 activity using a commercially available screening kit for CYP3A4 inhibitors and a human hepatocyte, HepaRG. Moreover, in order to estimate the interactions of these drugs with human P-gp, screening for substrates was performed. For some substrates, P-gp inhibition tests were carried out using P-gp-expressing MDCK cells. As a result, almost all the compounds showed the expected effects on human CYP3A4 both in the in vitro screening and in HepaRG cells. Importantly, the unproven mechanisms of DDIs caused by WHO group 5 drugs, thioamides, and p-aminosalicylic acid were elucidated. Intriguingly, clofazimine (CFZ) exhibited weak inductive effects on CYP3A4 at >0.25 μM in HepaRG cells, while an inhibitory effect was observed at 1.69 μM in the in vitro screening, suggesting that CFZ autoinduces CYP3A4 in the human liver. Our method, based on one of the pharmacokinetics parameters in humans, provides more practical information associated with not only DDIs but also with drug metabolism.

Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Figures

FIG 1

Differences in the inhibitory effect of nevirapine (NVP) on CYP3A4 induction mediated by various CYP3A4 inducers. The inhibitory effects of NVP were estimated by the amount of production of 1-hydroxymidazolam. The experiments were carried out in triplicate, and the representative data (means ± standard deviations) of two separate experiments are shown. RIF, rifampin; RFB, rifabutin; EFV, efavirenz; PB, phenobarbital; CMZ, carbamazepine. The numbers in parentheses represent the exposed micromolar concentrations for each CYP3A4 inducer.