Changes in the metabolism of three model substrates catalysed by different P450 isozymes when administered as a cocktail to the carbon tetrachloride-intoxicated rat

Abstract

1. Caffeine (CA) metabolism in animal and man is mainly catalysed by P4501A2. Lidocaine (LID) and phenytoin (PHT) are metabolized by P4503A2 and 2B1/2 in animals and 3A4 and 2C9 in man, respectively.

2. We investigated the possibility of predicting liver damage from changes in blood concentrations after simultaneous i.v. administration (cocktail study) of the three probe drugs CA (10mg/kg), LID (4 mg/kg) and PHT (4mg/kg), and their main metabolites, paraxanthine (PX), monoethylglycinexylide (MEGX) and 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) respectively.

3. The metabolism of CA, LID and PHT and production of their metabolites (PX, MEGX and p-HPPH) in the carbon tetracholride (CCL₄ 0·25 and 0·5ml/kg)-treated rat were reduced in comparison with the control group.

4. The ratios (PX/CA and p-HPPH/PHT) of CA and PHT to the serum levels of the their metabolites 2h after i.v. administration of three drugs to the CCl₄-treated rat were significantly reduced.

5. The correlation coefficients among CLs of CA, LID and PHT, and the PX/CA and p-HPPH/PHT ratios in rat pretreated with different doses of CCL₄ are very high.

6. These results suggest that different estimates of hepatic oxidizing capacity, catalysed mainly by P4501A2, 2C and 3A, may be related to the extent of liver disease in the CCl₄-intoxicated rat. Therefore a ‘cocktail’ is not in fact needed to assess hepatic damage in the CCl₄-intoxicated rat.