Hepatotoxicity and toxicokinetics of ketoconazole in rabbits.
OBJECTIVE
To study the relationship between hepatotoxicity and toxicokinetics of ketoconazole in rabbits.


METHODS
Normal rabbits were given intragastric gavage ketoconazole 40, 80, and 160 mg/kg. Ketoconazole plasma concentrations were measured by high performance liquid chromatography. Toxicokinetic parameters were determined from the plasma concentration-time data with the 3P97 software package. Activities of serum glutamate-pyruvate-transaminase and glutamate-oxalate-transaminase and hepatic histopathological changes were observed at 36 h after administration. The relationship between hepatotoxicity and toxicokinetic parameters of ketoconazole was analyzed by linear correlation.


RESULTS
The concentration-time curves of three doses of ketoconazole fitted well into a two-compartment model. The proportional increase in the area under the plasma concentration-time curve (AUC) was more than that in the dose after the dose reached 80 mg/kg. Ketoconazole resulted in a marked elevation in the enzyme activities and significant damage of hepatocytes. Hepatotoxicity induced by ketoconazole was correlated to the dose, clearance (CL), maximum plasma concentration (Cmax), and most closely correlated to AUC when it was assessed by elevation transaminases in serum.


CONCLUSIONS
The severity of ketoconazole-induced hepatotoxicity was closely related to the exposure level (AUC) of the drug.
Ma
Yue-Ming
YM
School of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. maym@sh.cnuninet.net
Ma
Zhang-Qing
ZQ
Gui
Chang-Qing
CQ
Yao
Jian-She
JS
Sun
Rui-Yuan
RY
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000097:blood; D005260:Female; D007654:Ketoconazole / Q000493:pharmacokinetics / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011817:Rabbits
D000935:Antifungal Agents; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D007654:Ketoconazole