Multiple oral dosing of ketoconazole influences pharmacokinetics of quinidine after intravenous and oral administration in beagle dogs.
Multiple oral dosing of ketoconazole influences pharmacokinetics of quinidine after intravenous and oral administration in beagle dogs.
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DOI：
10.1111/j.1365-2885.2004.00610.x
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发表时间：
2004-10
影响因子：
1.3
通讯作者：
M. Kuroha;Y. Shirai;Minoru Shimoda
中科院分区：
文献类型：
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作者：
M. Kuroha;Y. Shirai;Minoru Shimoda
在这项研究中，我们研究了酮康唑（KTZ）多次口服给药对奎尼丁（QN）的药代动力学的影响，奎尼丁是一种CYP 3A底物，肝脏清除率低，静脉注射和口服给药后，在比格犬。4只犬经口给药。KTZ 20天（200 mg，b.i.d.）。QN静脉内（1 mg/kg）或口服给药。(100在KTZ治疗前10天和20天以及开始KTZ治疗后10天和20天，多次口服KTZ显著降低α和β，而增加t（1/2 β），V（1）和k（a）。KTZ治疗还显著降低了总体清除率（Cl（tot））和口服清除率（Cl（oral））。在KTZ存在下，未观察到生物利用度的显著变化。KTZ的联合给药使QN的C（max）增加至约1.5倍。静脉给药后的平均驻留时间（MRT（i. v.）），和口服给药后（MRT（p.o.））QN的平均吸收时间（MAT）缩短至50%。在KTZ存在下，QN的稳态分布容积（V（d（ss）不变。这些变化可能是由于KTZ抑制肝脏CYP 3A活性导致QN代谢减少。总之，KTZ多次经口给药在很大程度上影响了比格犬静脉给药和经口给药后QN的药代动力学。因此，临床给药方案中的KTZ可能会显著改变犬中主要由CYP 3A代谢的药物的药代动力学，肝脏清除率较低。在临床应用中，应注意KTZ与药物的合并给药，无论是p.o.或静脉
In this study, we investigated the effect of multiple oral dosing of ketoconazole (KTZ) on pharmacokinetics of quinidine (QN), a CYP3A substrate with low hepatic clearance, after i.v. and oral administration in beagle dogs. Four dogs were given p.o. KTZ for 20 days (200 mg, b.i.d.). QN was administered either i.v. (1 mg/kg) or p.o. (100 mg) 10 and 20 days before the KTZ treatment and 10 and 20 days after start of KTZ treatment. Multiple oral dosing of KTZ decreased significantly alpha and beta, whereas increased t(1/2beta), V(1), and k(a). The KTZ treatment also decreased significantly both total body clearance (Cl(tot)) and oral clearance (Cl(oral)). No significant change in bioavailability was observed in the presence of KTZ. Co-administration of KTZ increased C(max) of QN to about 1.5-fold. Mean resident time after i.v. administration (MRT(i.v.)), and after oral administration (MRT(p.o.)) of QN were prolonged to about twofold, whereas mean absorption time (MAT) was decreased to 50%. Volume of distribution at steady state (V(d(ss))) of QN was unchanged in the presence of KTZ. These alterations may be because of a decrease in metabolism of QN by inhibition of KTZ on hepatic CYP3A activity. In conclusion, multiple oral dosing of KTZ affected largely pharmacokinetics of QN after i.v. and oral administration in beagle dogs. Therefore, KTZ at a clinical dosing regimen may markedly change the pharmacokinetics of drugs primarily metabolized by CYP3A with low hepatic clearance in dogs. In clinical use, much attention should be paid to concomitant administration of KTZ with the drug when given either p.o. or i.v.