Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Heidelberg, Germany.
J Clin Pharmacol. 2021 Jun;61(6):789-798. doi: 10.1002/jcph.1789. Epub 2020 Dec 19.
Omeprazole is an established probe drug to assess cytochrome P450 (CYP) 2C19 activity (phenotyping). Because it has nonlinear pharmacokinetics (PK) after oral administration (autoinhibition of metabolism), the true impact of coadministered perpetrators on CYP2C19 substrates might be underestimated after regular doses. We tested the dose linearity of an intravenous omeprazole microdose of 100 µg and compared it with a 20-mg dose in 4 healthy poor metabolizers (PMs) and 6 extensive metabolizers (EMs) of CYP2C19 in the presence and absence of a strong inhibitor (voriconazole). Without voriconazole, omeprazole exposure was dose-proportional irrespective of the genotype, but in PMs geometric mean ratios (GMRs) of AUC were 6.6-fold higher and molar metabolic ratios of 5-OH omeprazole/omeprazole approximately 10-fold lower. Voriconazole increased omeprazole exposure in EMs approximately 5-fold (AUC GMR after 100 µg omeprazole, 4.61; 90% confidence interval [CI], 2.69-7.89; AUC GMR after 20 mg omeprazole, 5.5; 90%CI, 1.07-1.46), whereas no clinically significant impact on PK in PMs was observed (GMR AUC after 100 µg omeprazole, 1.29; 90%CI, 0.81-2.04; GMR AUC after 20 mg omeprazole, 1.25; 90%CI, 1.07-1.46). Linear regression and Bland-Altman analyses revealed excellent agreement between AUC and AUC of omeprazole (r = 0.987; bias, 0.35%; 95%CI, -3.197% to 3.89%) and also the molar metabolic ratio, 5-OH omeprazole/omeprazole (r = 0.987; bias, -3.939; 95%CI, -9.06% to -1.18%), suggesting that an abbreviated sampling protocol can be used for intravenous CYP2C19 phenotyping and drug interaction studies. In conclusion, the PK of intravenous omeprazole microdoses closely reflects the changes observed with regular omeprazole doses; however, to avoid autoinhibition of probe drugs, microdosing appears to be the favorable technique.
奥美拉唑是评估细胞色素 P450（CYP）2C19 活性（表型）的既定探针药物。由于口服后其药代动力学（PK）呈非线性（代谢自动抑制），因此在常规剂量下，共同给予的加害人对 CYP2C19 底物的真正影响可能被低估。我们测试了静脉注射奥美拉唑微剂量 100μg 的剂量线性，并在 4 名 CYP2C19 弱代谢者（PM）和 6 名广泛代谢者（EM）中比较了它与 20mg 剂量的情况，存在和不存在强抑制剂（伏立康唑）。没有伏立康唑时，无论基因型如何，奥美拉唑的暴露量均呈剂量比例，但 PM 的 AUC 几何均数比（GMR）高 6.6 倍，5-OH 奥美拉唑/奥美拉唑的摩尔代谢比约低 10 倍。伏立康唑使 EM 中的奥美拉唑暴露量增加约 5 倍（奥美拉唑 100μg 后 AUC GMR，4.61；90%置信区间[CI]，2.69-7.89；奥美拉唑 20mg 后 AUC GMR，5.5；90%CI，1.07-1.46），而在 PM 中对 PK 无明显影响（奥美拉唑 100μg 后 AUC GMR，1.29；90%CI，0.81-2.04；奥美拉唑 20mg 后 AUC GMR，1.25；90%CI，1.07-1.46）。线性回归和 Bland-Altman 分析显示奥美拉唑 AUC 与 AUC（r = 0.987；偏差，0.35%；95%CI，-3.197%至 3.89%）以及摩尔代谢比 5-OH 奥美拉唑/奥美拉唑（r = 0.987；偏差，-3.939；95%CI，-9.06%至-1.18%）之间具有良好的一致性，表明可以使用简化的采样方案进行静脉内 CYP2C19 表型和药物相互作用研究。总之，静脉内奥美拉唑微剂量的 PK 紧密反映了常规奥美拉唑剂量观察到的变化；然而，为了避免探针药物的自动抑制，微剂量似乎是有利的技术。
