Effects of cysteine on the pharmacokinetics of itraconazole in rats with protein-calorie malnutrition.
The effects of cysteine on the pharmacokinetics of itraconazole were investigated after intravenous, 20 mg/kg, and oral, 50 mg/kg, administration of the drug to control rats (fed for 4 weeks on 23% casein diet) and rats with PCM (protein-calorie malnutrition, fed for 4 weeks on 5% casein diet) and PCMC (PCM with oral cysteine supplementation, 250 mg/kg, twice daily during the fourth week). After intravenous administration of itraconazole to rats with PCM, the area under the plasma concentration-time curve from time zero to time infinity (AUC) of itraconazole was significantly greater (3580 compared with 2670 and 2980 microg min/ml) than those in control rats and rats with PCMC (the values between control rats and rats with PCMC were not significantly different). The above data suggested that metabolism of itraconazole decreased significantly in rats with PCM due to suppression of hepatic microsomal cytochrome p450 (CYP) 3A23 in the rats. The results could be expected since in rats with PCM, the level of CYP3A23 decreased significantly as compared to control. Itraconazole was reported to be metabolized via CYP3A4 to several metabolites, including hydroxyitraconazole, in human subjects. Human CYP3A4 and rat CYP3A1 (CYP3A23) proteins have 73% homology. By cysteine supplementation (rats with PCMC), the AUC of itraconazole was restored fully to control levels.
Lee
Ae K
AK
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, Republic of Korea.
Ahn
Choong Y
CY
Kim
Eun J
EJ
Kwon
Jong W
JW
Kim
Sang G
SG
Chung
Suk J
SJ
Shim
Chang-K
CK
Lee
Myung G
MG
D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D003545:Cysteine / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D004347:Drug Interactions; D007275:Injections, Intravenous; D017964:Itraconazole / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D011502:Protein-Energy Malnutrition / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000935:Antifungal Agents; D017964:Itraconazole; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; D003545:Cysteine