Caldwell Gary W, Ritchie David M, Masucci John A, Hageman William, Cotto Carlos, Hall Jeffrey, Hasting Becki, Jones William
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh & McKean Roads, P.O. Box 776, Spring House, PA 19477, USA.
Eur J Drug Metab Pharmacokinet. 2005 Jan-Jun;30(1-2):75-83. doi: 10.1007/BF03226411.
Since drug candidates with low oral systemic exposure may be due to either or both absorption and metabolism factors, determining what factors limit the oral systemic exposure is not always obvious in a single in-vivo pharmacokinetic (PK) assay. A rapid rat in-vivo PK screen where the oxidative drug metabolism has been attenuated using the suicide CYP450 inhibitor aminobenzotriazole (ABT) is described. We have shown that the roles of absorption and metabolism for drug candidates with low oral systemic exposure can be determined by comparing the PK parameters of drug candidates orally administered to non-treated and ABT-treated rats. Propranolol, metoprolol and climetidine are used as model drugs. Propranolol and metoprolol have low oral systemic exposures in rats primarily due to metabolism factors while the oral systemic exposure of climetidine is high in rats. For propranolol and metoprolol, large increases in the systemic exposure of these drugs were observed between non-treated and ABT-treated rats. ABT appeared not to increase or decrease significantly the rate and extent of absorption or metabolism of cimetidine since that oral systemic exposure of non-treated and ABT-treated rats did not significantly change. These experiments suggest that for drug candidates with low systemic exposures in rats an observation of no change in the oral systemic exposure in ABT-treated rats when compared to the non-treated rats imply that absorption (or formulation) factors limit the systemic exposure of the drug while an increase in the systemic exposure in ABT-treated rats imply that metabolism factors limit the systemic exposure. Due to the ease of preparing and interpreting PK data from ABT-treated rats, is suggested that this assay could be used as an alternative to in vivo cannulation assays.
由于口服全身暴露量低的候选药物可能是由吸收和代谢因素中的一个或两个导致的，因此在单一的体内药代动力学（PK）试验中，确定哪些因素限制口服全身暴露量并不总是显而易见的。本文描述了一种快速的大鼠体内PK筛选方法，该方法使用自杀性CYP450抑制剂氨基苯并三唑（ABT）来减弱氧化药物代谢。我们已经表明，通过比较口服给药于未处理和ABT处理大鼠的候选药物的PK参数，可以确定吸收和代谢对口服全身暴露量低的候选药物的作用。普萘洛尔、美托洛尔和西咪替丁用作模型药物。普萘洛尔和美托洛尔在大鼠中的口服全身暴露量低主要是由于代谢因素，而西咪替丁在大鼠中的口服全身暴露量高。对于普萘洛尔和美托洛尔，在未处理和ABT处理的大鼠之间观察到这些药物的全身暴露量大幅增加。ABT似乎没有显著增加或降低西咪替丁的吸收或代谢速率和程度，因为未处理和ABT处理的大鼠的口服全身暴露量没有显著变化。这些实验表明，对于在大鼠中全身暴露量低的候选药物，与未处理的大鼠相比，观察到ABT处理的大鼠口服全身暴露量没有变化意味着吸收（或制剂）因素限制了药物的全身暴露，而ABT处理的大鼠全身暴露量增加意味着代谢因素限制了全身暴露。由于从ABT处理的大鼠中制备和解释PK数据很容易，因此建议该试验可作为体内插管试验的替代方法。
