title: 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.
authors.affiliation: Department of Pathophysiology and Host Defense, Japan Anti-Tuberculosis Association, Research Institute of Tuberculosis, Kiyose, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Horita
authors.affiliation: Department of Pathophysiology and Host Defense, Japan Anti-Tuberculosis Association, Research Institute of Tuberculosis, Kiyose, Tokyo, Japan ndoi@jata.or.jp.
authors.forename: Norio
authors.initials: N
authors.lastname: Doi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000494:pharmacology*; D002460:Cell Line; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D004285:Dogs; D006801:Humans; D061985:Madin Darby Canine Kidney Cells
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D065692:Cytochrome P-450 CYP3A Inhibitors