Pharmacokinetic Drug Interaction between Tofacitinib and Voriconazole in Rats
| Autor: | Hyeon-Gyeom Choi, So Hee Kim, Hyo-Sung Kim, Yong-Seob Jung, Ji-Sang Lee |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
CYP2C
Antifungal drug Pharmaceutical Science Pharmacology 030226 pharmacology & pharmacy Article 03 medical and health sciences 0302 clinical medicine Pharmacy and materia medica Pharmacokinetics Oral administration non-competitive inhibition medicine voriconazole CYP3A Janus kinase inhibitor Voriconazole drug interaction Tofacitinib tofacitinib CYP3A4 business.industry Drug interaction RS1-441 030220 oncology & carcinogenesis business pharmacokinetics medicine.drug |
| Zdroj: | Pharmaceutics, Vol 13, Iss 740, p 740 (2021) Pharmaceutics Volume 13 Issue 5 |
| ISSN: | 1999-4923 |
| Popis: | Fungal infections are prevalent in patients with immune diseases. Voriconazole, a triazole antifungal drug, inhibits the cytochromes CYP3A4 and CYP2C, and tofacitinib, a Janus kinase inhibitor for the treatment of rheumatoid arthritis, is metabolized by CYP3A4 and CYP2C19 in humans. Here, we investigated their interaction during simultaneous administration of both drugs to rats, either intravenously or orally. The area under the plasma concentration–time curve from time zero to time infinity (AUC) of tofacitinib was significantly greater, by 166% and 171%, respectively, and the time-averaged non-renal clearance (CLNR) of tofacitinib was significantly slower (59.5%) than that for tofacitinib alone. An in vitro metabolism study showed non-competitive inhibition of tofacitinib metabolism in the liver and intestine by voriconazole. The concentration/apparent inhibition constant (Ki) ratios of voriconazole were greater than two, indicating that the inhibition of tofacitinib metabolism could be due to the inhibition of the CYP3A1/2 and CYP2C11 enzymes by voriconazole. The pharmacokinetics of voriconazole were not affected by the co-administration of tofacitinib. In conclusion, the significantly greater AUC and slower CLNR of tofacitinib after intravenous and oral administration of both drugs were attributable to the non-competitive inhibition of tofacitinib metabolism via CYP3A1/2 and CYP2C11 by voriconazole in rats. |
| Databáze: | OpenAIRE |
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