Fayer J L, Zannikos P N, Stevens J C, Luo Y, Sidhu R, Kirkesseli S
Department of Drug Metabolism and Pharmacokinetics of Aventis Pharma, Collegeville, Pennsylvania, USA.
J Clin Pharmacol. 2001 Mar;41(3):305-16. doi: 10.1177/00912700122010122.
RG 12525 (2-[[4-[[2-(1H-tetrazole-5-ylmethyl)phenyl]methoxy]phenoxy]methyl] quinolone) is a novel peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist. In vitro microsomal inhibition assays indicated that RG 12525 is a potent inhibitor of CYP3A4, with a Ki value of 0.5 microM. With the conservative assumption that the total plasma concentration of drug was available to metabolic enzymes following RG 12525 oral administration, marked inhibition of CYP3A4 was expected to substantially reduce the systemic clearance of compounds metabolized by this enzyme. The possibility also existed for inhibition of intestinal and hepatic CYP3A4 by RG 12525 to reduce "first-pass" metabolism and increase absolute bioavailability of CYP3A4 substrates orally coadministered. Consequently, an in vivo drug-drug interaction study was performed to evaluate the effects of orally administered RG 12525 on in vivo CYP3A4 activity in healthy male subjects. The pharmacokinetics of oral midazolam, a probe for intestinal and hepatic CYP3A activity, was not influenced by either the low (100 mg qd for 4 days) or high (600 mg qd for4 days) RG 12525 dosing regimen despite the resulting total plasma concentrations of inhibitor that were well above in vitro Ki values. The point estimates and 90% confidence intervals for the ratios of mean midazolam AUC for subjects administered 100 mg RG 12525 (110.6; 98.7-124.1) and 600 mg RG 12525 (98.4; 84.4-114.7) versus midazolam alone were within 80% to 125%. To explain these results, factors that could limit the accuracy of in vitro models in predicting metabolic drug interactions, mainly the high degree of RG 12525 protein binding (> 99.9%), were considered. The lack of correlation between the in vitro inhibition of CYP3A4 by RG 12525 and the inconsequential effects of this compound on midazolam pharmacokinetics accentuate the need to recognize factors other than plasma drug concentrations and potency of in vitro enzyme inhibition when extrapolating in vitro data to predict in vivo drug-drug interactions.
RG 12525（2-[[4-[[2-(1H-四氮唑-5-基甲基)苯基]甲氧基]苯氧基]甲基]喹诺酮）是一种新型过氧化物酶体增殖物激活受体γ（PPAR-γ）激动剂。体外微粒体抑制试验表明，RG 12525是CYP3A4的强效抑制剂，Ki值为0.5微摩尔。基于保守假设，即RG 12525口服给药后药物的总血浆浓度可被代谢酶利用，预计CYP3A4的显著抑制会大幅降低该酶代谢的化合物的全身清除率。RG 12525抑制肠道和肝脏CYP3A4从而降低“首过”代谢并增加口服共同给药的CYP3A4底物的绝对生物利用度的可能性也存在。因此，进行了一项体内药物相互作用研究，以评估口服RG 12525对健康男性受试者体内CYP3A4活性的影响。口服咪达唑仑（一种肠道和肝脏CYP3A活性的探针）的药代动力学不受低剂量（100毫克/天，共4天）或高剂量（600毫克/天，共4天）RG 12525给药方案的影响，尽管由此产生的抑制剂总血浆浓度远高于体外Ki值。接受100毫克RG 12525（110.6；98.7 - 124.1）和600毫克RG 12525（98.4；84.4 - 114.7）的受试者与单独使用咪达唑仑相比，咪达唑仑AUC比值的点估计值和90%置信区间在80%至125%之间。为了解释这些结果，考虑了可能限制体外模型预测药物代谢相互作用准确性的因素，主要是RG 12525的高蛋白结合率（>99.9%）。RG 12525在体外对CYP3A4的抑制与该化合物对咪达唑仑药代动力学无关紧要的影响之间缺乏相关性，这突出表明在推断体外数据以预测体内药物相互作用时，需要认识到除血浆药物浓度和体外酶抑制效力之外的其他因素。
