Meredith C G, Maldonado A L, Speeg K V
Drug Metab Dispos. 1985 Mar-Apr;13(2):156-62.
Ketoconazole is a new antifungal drug which has increasing clinical application due to its wide spectrum of activity and oral availability. Since substituted imidazoles may be potent inhibitors of cytochrome-mediated drug oxidation, we have examined the effect of ketoconazole on aminopyrine and caffeine metabolism in the rat. The 14C breath test was used to determine the elimination rate of aminopyrine and caffeine in vivo after single and chronic (7 day) treatment with ketoconazole. Acutely, ketoconazole (50 mg/kg) impaired markedly both aminopyrine (56% inhibition) and caffeine demethylation (83% inhibition). Inhibition of aminopyrine and caffeine demethylation as studied with the breath tests was related to ketoconazole dose. The decreased rate of aminopyrine demethylation measured by breath test correlated with decreased aminopyrine clearance from plasma after iv dosage. Chronic treatment with ketoconazole further increased the inhibition of aminopyrine demethylation while chronic treatment was associated with less inhibition of caffeine demethylation than found with a single dose. Breath tests repeated up to 72 hr after ketoconazole treatment revealed differences in aminopyrine and caffeine demethylation. At 24 hr after ketoconazole, aminopyrine demethylation was still inhibited at 78% of controls whereas caffeine demethylation was enhanced to 146% of control. Binding of ketoconazole to microsomal P-450 was determined by spectral analysis. A type II difference spectrum was found with absorbance maximum at 430 nm and minimum at 390 nm. Scatchard analysis revealed a biphasic interaction with estimated dissociation constants of 0.6 and 3.69 microM. Aminopyrine N-demethylation in vitro was markedly impaired with an I50 for ketoconazole of 27 microM and Ki of 8.5 microM.(ABSTRACT TRUNCATED AT 250 WORDS)
酮康唑是一种新型抗真菌药物，因其广泛的活性谱和口服可用性而在临床上的应用日益增加。由于取代咪唑可能是细胞色素介导的药物氧化的强效抑制剂，我们研究了酮康唑对大鼠氨基比林和咖啡因代谢的影响。采用14C呼气试验来测定单次和长期（7天）给予酮康唑后体内氨基比林和咖啡因的消除率。急性给药时，酮康唑（50mg/kg）显著损害氨基比林（抑制56%）和咖啡因去甲基化（抑制83%）。通过呼气试验研究发现，氨基比林和咖啡因去甲基化的抑制与酮康唑剂量有关。呼气试验测得的氨基比林去甲基化速率降低与静脉给药后血浆中氨基比林清除率降低相关。酮康唑长期治疗进一步增加了对氨基比林去甲基化的抑制，而长期治疗对咖啡因去甲基化的抑制作用比单次给药时小。酮康唑治疗后长达72小时重复进行呼气试验，结果显示氨基比林和咖啡因去甲基化存在差异。酮康唑给药后24小时，氨基比林去甲基化仍被抑制在对照组的78%，而咖啡因去甲基化则增强至对照组的146%。通过光谱分析测定酮康唑与微粒体P-450的结合。发现一种II型差示光谱，最大吸收波长为430nm，最小吸收波长为390nm。Scatchard分析显示存在双相相互作用，估计解离常数为0.6和3.69μM。体外氨基比林N-去甲基化明显受损，酮康唑的I50为27μM，Ki为8.5μM。（摘要截短至250字）
