RESUMEN
Most medications undergo metabolism and elimination via CYP450 enzymes, while uptake and efflux transporters play vital roles in drug elimination from various organs. Interactions often occur when multiple drugs share CYP450-transporter-mediated metabolic pathways, necessitating a unique clinical care strategy to address the diverse types of CYP450 and transporter-mediated drug-drug interactions (DDI). The primary focus of this review is to record relevant mechanisms regarding DDI between COVID-19 and tuberculosis (TB) treatments, specifically through the influence of CYP450 enzymes and transporters on drug absorption, distribution, metabolism, elimination, and pharmacokinetics. This understanding empowers clinicians to prevent subtherapeutic and supratherapeutic drug levels of COVID medications when co-administered with TB drugs, thereby mitigating potential challenges and ensuring optimal treatment outcomes. A comprehensive analysis is presented, encompassing various illustrative instances of TB drugs that may impact COVID-19 clinical behavior, and vice versa. This review aims to provide valuable insights to healthcare providers, facilitating informed decision-making and enhancing patient safety while managing co-infections. Ultimately, this study contributes to the body of knowledge necessary to optimize therapeutic approaches and improve patient outcomes in the face of the growing challenges posed by infectious diseases.
RESUMEN
Clofazimine [N,5-bis(4-chlorophenyl)-3-[(propane-2-yl)rimino]-3,5-dihydrophenazin-2-amine] is an antimycobacterial agent used as a second-line antituberculosis (anti-TB) drug. Nonetheless, little information is known about the metabolic routes of clofazimine, and the enzymes involved in metabolism. This study aimed to characterize the metabolic pathways and enzymes responsible for the metabolism of clofazimine in human liver microsomes. Eight metabolites, including four oxidative metabolites, three glucuronide conjugates, and one sulfate conjugate were identified, and their structures were deduced based on tandem mass spectrometry (MS/MS) spectra. Hydroxylated clofazimine and hydrated clofazimine was generated even in the absence of the NADPH generating system presumably via a nonenzymatic pathway. Hydrolytic-dehalogenated clofazimine was catalyzed mainly by CYP1A2 whereas hydrolytic-deaminated clofazimine was formed by CYP3A4/A5. In case of glucuronide conjugates, UGT1A1, UGT1A3, and UGT1A9 showed catalytic activity toward hydroxylated and hydrated clofazimine glucuronide whereas hydrolytic-deaminated clofazimine glucuronide was catalyzed by UGT1A4, UGT1A9, UGT1A3, and UGT2B4. Our results suggested that CYP1A2 and CYP3A are involved in the formation of oxidative metabolites while UGT1A1, 1A3, 1A4, 1A9, and 2B4 are involved in the formation of glucuronide conjugates of oxidative metabolites of clofazimine.
Asunto(s)
Glucurónidos , Microsomas Hepáticos , Humanos , Microsomas Hepáticos/metabolismo , Glucurónidos/química , Citocromo P-450 CYP1A2 , Citocromo P-450 CYP3A/metabolismo , Clofazimina/metabolismo , Espectrometría de Masas en Tándem , NADP/metabolismo , Propano/metabolismo , Glucuronosiltransferasa , Sulfatos/metabolismo , Aminas/metabolismo , Antibacterianos/metabolismo , Hígado/metabolismoRESUMEN
In this study, we explored clofazimine (CFZ) as a potential substrate of uptake and efflux transporters that might be involved in CFZ disposition, using transporter gene overexpressing cell lines in vitro. The intracellular concentrations of CFZ were significantly increased in the presence of selective inhibitors of P-gp and BCRP, which include verapamil, cyclosporine-A, PSC-833, quinidine, Ko143, and daunorubicin. In a bidirectional transport assay using transwell cultures of cell lines overexpressing P-gp and BCRP, the mean efflux ratios of CFZ were found to be 4.17 ± 0.63 and 3.37 ± 1.2, respectively. The Km and maximum rate of uptake (Vmax) were estimated to be 223.3 ± 14.73 µM and 548.8 ± 87.15 pmol/min/mg protein for P-gp and 381.9 ± 25.07 µM and 5.8 ± 1.22 pmol/min/mg protein for BCRP, respectively. Among the uptake transporters screened, the CFZ uptake rate was increased 1.93 and 3.09-fold in HEK293 cell lines overexpressing OAT1 and OAT3, respectively, compared to the control cell lines, but no significant uptake was observed in cell lines overexpressing OCT1, OCT2, OATP1B1, OATP1B3, OATP2B1, or NTCP. Both OAT1- and OAT3-mediated uptake was inhibited by the selective inhibitors diclofenac, probenecid, and butanesulfonic acid. The Km and Vmax values of CFZ were estimated to be 0.63 ± 0.15 µM and 8.23 ± 1.03 pmol/min/mg protein, respectively, for OAT1 and 0.47 ± 0.1 µM and 17.81 ± 2.19 pmol/min/mg protein, respectively, for OAT3. These findings suggest that CFZ is a novel substrate of BCRP, OAT1, and OAT3 and a known substrate of P-gp in vitro.