Rajnarayana K, Reddy Mada S, Krishna Devarakonda R
Drug Metabolism and Clinical Pharmacokinetics Division, University College of Pharmaceutical Sciences, Kakatiya University, AP-506009, Warangal, India.
Eur J Clin Pharmacol. 2003 Apr;58(12):803-7. doi: 10.1007/s00228-002-0543-5. Epub 2003 Mar 1.
To screen for inhibitory effects of diosmin on cytochrome P(450)-mediated metabolism of metronidazole in healthy volunteers.
Before/after non-blinded investigation conducted in healthy male volunteers.
After an overnight fast, metronidazole (two 400-mg tablets) was administered to 12 volunteers, either alone or after a 9-day pretreatment period with a once-daily dose of diosmin 500-mg tablets under direct observation. Serum concentrations of metronidazole up to 48 h postdose and urinary concentrations of metronidazole and its two major metabolites up to 24 h postdose were measured using reversed-phase high-performance liquid chromatography.
Metronicazole plasma AUC((0- infinity )) and C(max) were significantly higher after diosmin pretreatment by (mean) 27% and 24%, respectively. However, time to reach peak concentration (t(max)) was not affected significantly. Urinary excretion of acid and hydroxy metabolites in urine was decreased significantly, while excretion of unchanged metronidazole was increased.
Diosmin pretreatment significantly altered the metabolism of metronidazole, as demonstrated by changes in plasma pharmacokinetics as well as by urinary recovery of both parent drug and its major metabolites. This may be caused by the inhibition of cytochrome P(450) enzymes.
筛选地奥司明对健康志愿者体内细胞色素P(450)介导的甲硝唑代谢的抑制作用。
在健康男性志愿者中进行的非盲法前后对照研究。
12名志愿者在禁食过夜后，单独服用甲硝唑（两片400毫克片剂），或在直接观察下，先每日一次服用500毫克地奥司明片剂进行为期9天的预处理后再服用甲硝唑。使用反相高效液相色谱法测定给药后48小时内甲硝唑的血清浓度以及给药后24小时内甲硝唑及其两种主要代谢物的尿液浓度。
地奥司明预处理后，甲硝唑血浆AUC((0-∞))和C(max)分别显著升高（平均）27%和24%。然而，达峰时间(t(max))未受到显著影响。尿液中酸性和羟基代谢物的排泄显著减少，而未改变的甲硝唑排泄增加。
地奥司明预处理显著改变了甲硝唑的代谢，这通过血浆药代动力学变化以及母体药物及其主要代谢物的尿液回收率得以证明。这可能是由细胞色素P(450)酶的抑制作用引起的。
