['HMETABOLISM', 'OF', 'METRONIDAZOLE', 'AND', 'ANTTPYRINE', 'IN', 'ISOLATED', 'HEPATOCYTES:', 'INFLUENCE', 'OF', 'SPECIES,', 'SEX', 'AND', 'ENZYME', 'INDUCERS', 'AND', 'INHIBITORS', "'S.", 'Loft', 'anéd', 'H.E.', 'Poulsen', '!', 'Department', 'of', 'Pharmacology,', 'University', 'of', 'Copenhagen,', 'Denmark', 'To', 'evaluate', 'metronicdazole', 'as', 'a', 'probe', 'for', 'the', 'study', 'of', 'drug', 'metabolism,', 'optionally', 'in', 'a', 'cocktail', 'with', 'antipyrine,', 'the', 'metabolism', 'of', 'these', 'two', 'drugs', 'was', 'investigated', 'in', 'freshly', 'isolated', 'hepatocytes', 'fram', '7', 'male', 'and', '6', 'female', 'control', 'Wistar', 'rats,', '8', 'male', 'and', '5', 'female', 'rats', 'pretreated', 'with', 'phencbarbital', '(PB),', '3', 'male', 'rats', 'pretreated', 'with', '3-methylcholanthrene', '(MC)', 'and', '6', 'groups', 'of', '2-3', 'Theiler', 'mice.', 'The', 'formation', 'rate', 'of', 'metabolites', 'fram', 'both', 'drugs', 'followed', 'Michaelis~lienten', 'kinetics.', 'The', 'average', 'Xm', 'values', 'for', 'the', 'formation', 'of', 'the', 'major', 'metronidazole', 'rmetabolites', 'ranged', 'from', '1', 'to', '3', 'mM.', 'The', 'intrinsic', 'clearance', '(CLi=Vmax/Im)', 'for', 'formation', 'of', 'the', 'oxidated', 'acetic', 'acid', '(MAR)', 'and', 'hydroxy', '(HM)', 'metabolites', 'and', 'the', 'glucuronide', 'conjugate', 'of', 'metronidazole', 'was', '21', '(12-28)', 'wvs', '58', '(18-125;', 'g£', '0.05),', '42', '(23-52)', 'vs', '156', '(63-263;', 'pf£0.05)', 'and', '687', '(390-1616)', 'vs', '269', '(102~', '452;', '£0.05)', 'nl/min', 'per', '106', 'rat', 'and', 'mouse', 'hepatocytes,', 'respectively', '(median', 'with', 'range,', 'n=6).', 'Pretreatment', 'with', 'PB', 'increased', 'CLi', 'of', 'metronidazole', 'to', 'MRA', 'and', 'HM', '7-', 'and', '2.8-fold', 'in', 'the', 'male', 'and', '3.2-', 'and', '3.0-fold', 'in', 'the', 'female', 'rats,', 'whereas', 'IMC', 'pretreatment', 'increased', 'the', 'values', '9~', 'and', '10-fold,', 'respectively', '(p<0.05).', 'The', 'CLi', 'to', 'HM', 'was', '0.5-fold', 'lower', 'in', 'the', 'female', 'than', 'in', 'the', 'corresponding', 'male', 'groups', '(p', '<0.05).', 'The', 'CLi', 'for', 'glucuronidation', 'of', 'metronicdazole', 'was', 'higher', 'in', 'the', 'two', 'male', 'than', 'in', 'the', 'corresponding', 'female', 'groups,', 'whereas', 'the', 'rank', 'orcer', 'was', 'reversed', 'for', 'the', 'formation', 'of', 'sulphate', '(pKX0.05).', 'SKF', '525A', 'was', 'more', 'potent', 'as', 'inhibitor', 'of', 'MAA', 'formation', 'than', 'of', 'HM', 'formation,', 'except', 'in', 'the', 'PB', 'treated', 'male', 'group.', 'Pretreatment', 'with', 'MC', 'increased', 'the', 'potency', 'of', '7,8-', 'benzoflavone', 'and', 'antipyrine', 'for', 'inhibition', 'of', 'the', 'formation', 'of', 'MAA', 'and', 'HM.', 'The', 'average', 'Xm', 'values', 'for', 'the', 'formation', 'of', 'antipyrine', 'metablites', 'ranged', 'from', '2', 'to', '10', 'mM.', 'The', 'intrinsic', 'clearance', 'for', 'production', 'of', 'hydroxymethyl-', '(HMAP),', 'nor-', '(NORAP)', 'and', 'hydroxyantipyrine', '(OHAP)', 'was', '487', '(296~793)', 'vs', '232', '(43-519;', 'p', '<0.05),', '92.6', '(55-180)', 'vs', '594', '(168-813;', 'pX0.05)', 'and', '239', '(134-501)', 'vs', '(118', '(23-505;', 'f', '0.05)', 'nl/min', 'per', '106', 'rat', 'and', 'mouse', 'hepatocytes,', 'respecti-', 'vely', '(median', 'with', 'range,', 'n=6).', '‘In', 'the', 'male', 'rats', 'PB', 'pretreatment', 'increased', 'CLi', 'to', 'HMAP,', 'MNORAP', 'and', 'OHAP', '2', '5;-,', '2.1-', 'and', '4.5-fold,', 'respectively', '(p<0.05),', 'whereas', 'MC', 'and', 'in', 'the', 'emales', 'PB', 'pretreatment', 'had', 'no', 'significant', 'effects', 'on', 'antipyrine', 'metabo-', 'ism.', 'SKF', '525A', 'was', 'more', 'potent', 'as', 'inhibitor', 'of', 'HMAP', 'and', 'OHAP', 'formation', 'than', '/of', 'NORAP', 'formation,', 'except', 'in', 'the', 'PB', 'treated', 'male', 'group.', 'Pretreatment', 'with', 'MC', 'increased', 'the', 'potency', 'of', '7,8-benzoflavone', 'for', 'inhibition', 'of', 'the', 'formation', 'of', 'all', 'antipyrine', 'metabolites.', 'Coincubation', 'with', 'metronidazole', 'increased', 'the', 'formation', 'of', 'HMAP,', 'but', 'inhibited', 'the', 'formation', 'of', 'NORAP', 'and', 'OHAP,', 'particu-', 'larly', 'the', 'latter.', 'It', 'is', 'concluded', 'that', 'the', 'formation', 'of', 'MAA,', 'HM,', 'HMAP,', 'NORAP', 'and', 'OHAP', 'from', 'metronidazole', 'and', 'antipyrine', 'may', 'be', 'catalyzed', 'by', 'different', 'cytochrame', 'P-450', 'isozymes,_', 'which', 'may', 'be', 'suplemented', 'or', 'substituted', 'by', 'PB', 'or', 'MC', 'induced', 'species', 'and', 'have', 'more', 'or', 'less', 'overlapping', 'substrate', 'and', 'product', 'specifici-', 'ty.', 'Metronidazole', 'appears', 'to', 'be', 'a', 'sensitive', 'probe', 'for', 'detection', 'and', ')', 'icdentification', 'PB', 'and', 'IMC', 'type', 'enzyme', 'induction.', '199006820', 'V)']