PHASE-I AND PHASE-II XENOBIOTIC BIOTRANSFORMATION IN DIFFERENT INBREDSTRAINS OF RATS - STUDY IN IMMOBILIZED PERFUSED HEPATOCYTES

The present study was designed to compare phase I and phase TI biotran sformation reactions in immobilized perfused hepatocytes as a cellular system obtained from inbred rat strains which represent models for so me cardiovascular diseases, namely, spontaneously hypertensive rats (S HR), rats sensitive and resistant to isoprenaline-induced myocardial l esions (IS and IR, respectively) as compared to Wistar rats (W). The b iotransformation kinetics for hexobarbital (HX), 7-ethoxycoumarin (7-E C), 1-chloro-2,4-dinitrobenzene (CDNB) and 4-nitrophenol. (4-NP) were followed up in the hepatocyte perfusate, W and SHR rat hepatocytes hav e metabolized HX at a higher rate than those of the IR and IS strains, Hepatocytes from the W strain exhibited a higher rate of 7-EC deethyl ation activity compared to hepatocytes obtained from the IR or IS stra ins. Hepatocytes obtained from SHR and IR rats showed the highest glut athione-S-transferase (GST) activity towards CDNB compared to the IS o r W strain. 4-NP disappearance was higher in the perfusion medium of h epatocytes obtained from the W and IS strains compared to the IR strai n, These significant differences in drug biotransformation between var ious studied strains, which may be genetically determined, can be well demonstrated by using an efficient drug metabolizing model of the imm obilized perfused hepatocytes, The importance of these differences sho uld be considered during the study of the experimental therapy of the relevant disease as obtained from the specific experimental strain, wh ere it may be expected that the pharmacokinetic profile of a drug in v ivo and consequently its pharmacodynamic or toxic effects mill be stra in dependent.