Yu C. Kim

Dose-Dependent Pharmacokinetics of Itraconazole after Intravenous or Oral Administration to Rats: Intestinal First-Pass Effect

ABSTRACT The dose-dependent pharmacokinetics of itraconazole after intravenous (10, 20, or 30 mg/kg) and oral (10, 30, or 50 mg/kg) administration and the first-pass effects of itraconazole after intravenous, intraportal, intragastric, and intraduodenal administration at a dose of 10 mg/kg were evaluated in rats. After intravenous administration at a dose of 30 mg/kg, the area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) was significantly greater than those at 10 and 20 mg/kg (1,090, 1,270, and 1,760 μg · min/ml for 10, 20, and 30 mg/kg, dose-normalized at 10 mg/kg). After oral administration, the AUC0-∞ was significantly different for three oral doses (380, 687, and 934 μg · min/ml for 10, 30, and 50 mg/kg, respectively, dose-normalized at 10 mg/kg). The extent of absolute oral bioavailability (F) was 34.9% after an oral dose at 10 mg/kg. The AUC0-∞ (or AUC0-8 h) values were comparable between intravenous and intraportal administration and between intragastric and intraduodenal administration, suggesting that the hepatic and gastric first-pass effects were almost negligible in rats. However, the AUC0-8 h values after intraduodenal and intragastric administration were significantly smaller than that after intraportal administration, approximately 30%, suggesting that the intestinal first-pass effect was approximately 70% of that of an oral dose of 10 mg/kg. The low F after oral administration of itraconazole at a dose of 10 mg/kg could be mainly due to the considerable intestinal first-pass effect.

Effect of CYP3A1 (23) Induction on Clarithromycin Pharmacokinetics in Rats with Diabetes Mellitus

ABSTRACT After intravenous and oral administration of clarithromycin at a dose of 20 mg/kg of body weight to rats with diabetes mellitus induced by alloxan (DMIA) and diabetes mellitus induced by streptozotocin (DMIS), the area under the curve values were significantly smaller than those of respective control rats. The in vitro intrinsic clearance values for the disappearance of clarithromycin were significantly faster in both rats with DMIA and rats with DMIS than in control rats. The above data suggested that metabolism of clarithromycin increased in both types of diabetic rat due to an increase in the expression and mRNA level of CYP3A1(23) in the rats.

Pharmacokinetics of intravenous and oral DA-8159, a new erectogenic, in rats with protein-calorie malnutrition.

Influence of dietary protein deficiency on the pharmacokinetics of DA‐8159 and one of its metabolites, DA‐8164, was investigated after intravenous and oral administration of DA‐8159 at a dose of 30 mg kg−1 to male Sprague‐Dawley rats allowed free access to a 23% (control) or 5% (protein‐calorie malnutrition, PCM) casein diet for 4 weeks. The total area under the plasma concentration‐time curve from time zero to time infinity (AUC) values of DA‐8164 were significantly smaller after both intravenous (87.0 vs 162 μg min mL−1) and oral (144 vs 319 μg min mL−1) administration of DA‐8159 to PCM rats. This could be due to the decrease in CYP3A1/2 (50–60%) in the rats because DA‐8164 was mainly formed via CYP3A1/ 2 in rats. This could be supported by significantly slower in‐vitro CLint (2.04 ± 0.646 vs 3.15 ± 0.693 μL min−1 (mg protein)−1) for the formation of DA‐8164 in hepatic microsomal fraction of PCM rats. After intravenous administration of DA‐8159, the AUC values of DA‐8159 were not significantly different between the two groups of rats although the AUC of DA‐8164 was significantly smaller in PCM rats, and this may be due to the minor metabolic pathway of DA‐8164 in rats. However, after oral administration of DA‐8159, the AUC of DA‐8159 was significantly greater in PCM rats (194 vs 122 μg min mL−1). This was not due to enhanced absorption of DA‐8159 from the gastrointestinal tract in the rats but may be due to a decreased intestinal first‐pass effect of DA‐8159 in the rat.