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Levothyroxine, a synthetic form of thyroid hormone, has been clinically used to treat thyroid hormone deficiency. UDP-glucuronosyltransferases (UGTs) are important phase II drug-metabolizing enzymes, and UGTs-inhibition based drug-drug interaction has been widely reported. The aim of the present study is to investigate the inhibitory effect of levothyroxine towards UGT1A6-catalyzed 4-methylumbelliferone (4-MU) glucuronidation. The results showed that levothyroxine inhibited UGT1A6-catalyzed 4-MU glucuronidation reaction in a dose-dependent manner. Furthermore, Lineweaver-Burk and Dixon plots showed the inhibition of UGT1A6 by levothyroxine was best fit to competitive inhibition, and the inhibition kinetic parameter (Ki ) was determined to be 15.3 μM. Given that UGT1A6 is one of the most important UGT isoforms catalyzing the glucuronidation reaction of many important clinical drugs, including aspirin and serotonin, inhibition of UGT1A6 activity by levothyroxine will significantly influence the pharmacokinetic behaviour of these drugs. Therefore, clinical drug-drug interaction due to the inhibition of UGT1A6 by levothyroxine should paid much attention., Colegio de Farmacéuticos de la Provincia de Buenos Aires

Substrate-dependent inhibition of CYP3A4 might influence the extrapolation of drug interactions from the in vitro to in vivo situation. The aim of the present study is to investigate reversible and time-dependent inhibition of CYP3A4-mediated nifedipine oxidation by noscapine. Furthermore, in vitroin vivo extrapolation (IVIVE) was performed using in vitro parameters. The results showed that CYP3A4- mediated nifedipine oxidation activity was strongly inhibited with an IC50 of 25.7 ± 5.4 μM. Kinetic analysis showed that inhibition of CYP3A4-mediated nifedipine oxidation by noscapine was best fit to a noncompetitive manner with Ki value of 10.9 μM. IC50 shift experiment showed that IC50 was significantly decreased from 25.7 ± 5.4 μM to 0.34 ± 0.07 μM after pre-incubation with noscapine for 30 min, which indicated that time-dependent inhibition existed for inhibition of CYP3A4 by noscapine. The AUC of (R)- warfarin was predicted to increase by 0.5 % using Cmax or 0.2 % using unbound Cmax with reversible inhibition prediction equation, while the AUC of (R)-warfarin was estimated to increase by 23.1 % using Cmax or 10.4 % using unbound Cmax with TDI prediction equation. Inhibition of CYP3A4 by noscapine showed substrate-dependent inhibition behaviour. However, the results obtained from IVIVE are very similar using testosterone or nifedipine as probe substrates., Colegio de Farmacéuticos de la Provincia de Buenos Aires