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Deprenyl, a selective inhibitor of monoamine oxidase type B (MAO-B), was metabolized in rats to methamphetamine (MAP), amphetamine (AP) and their corresponding p-hydroxylated metabolites, p-hydroxy-MAP and p-hydroxy-AP. Recovery of metabolites in 24 h urine was 25% of the dose, and there was no urinary excretion of unchanged deprenyl. Deprenyl was converted into MAP, AP and nordeprenyl when incubated in vitro with rat-liver microsomes in the presence of NADPH. This metabolism was inhibited in an atmosphere of N2 and by CO, and by SKF 525-A, but to a lesser extent by methimazole. Liver microsomes from phenobarbital (PB)-treated rats, but not 3-methylcholanthrene (3-MC)-treated rats, stimulated the metabolism of deprenyl in vitro to MAP and AP, but not to nordeprenyl. In contrast, microsomes from SKF 525-A-treated rats showed decreased activity in the metabolism of deprenyl to all three metabolites. The inhibitory effect of the drug on hepatic MAO-B activity was annulled by pretreatment of rats with PB, but not 3-MC, and augmented by pretreatment with SKF 525-A.

Aims Mexiletine has been reported to be hydroxylated by cytochrome P450 2D6 (CYP2D6) in humans. However, the involvement of CYP1A2 in the metabolism of mexiletine has been proposed based on the interaction with theophylline which is mainly metabolized by CYP1A2. The aim of this study was to clarify the role of human CYP1A2 in mexiletine metabolism. Methods Human CYP isoforms involved in mexiletine metabolism were investigated using microsomes from human liver and B-lymphoblastoid cells expressing human CYPs. The contributions of CYP1A2 and CYP2D6 to mexiletine metabolism were estimated by the relative activity factor (RAF). Results Mexiletine p-and 2-hydroxylase activities in human liver microsomes were inhibited by ethoxyresorufin and furafylline as well as quinidine. Mexiletine p-and 2-hydroxylase activities in microsomes from nine human livers correlated significantly with bufuralol 1∞-hydroxylase activity (r=0.907, P<0.001 and r=0.886, P<0.01, respectively). Microsomes of B-lymphoblastoid cells expressing human CYP1A2 exhibited lower mexiletine p-and 2-hydroxylase activities than those expressing human CYP2D6. It was estimated by RAF that the major isoform involved in mexiletine metabolism was CYP2D6, and the contribution of CYP1A2 to both mexiletine p-and 2-hydroxylase activities was 7-30% in human liver microsomes. However, the K m values of the expressed CYP1A2 (~15 mm) were almost identical with those of the expressed CYP2D6 (~22 mm) and human liver microsomes. Conclusions Mexiletine is a substrate of CYP1A2. The data obtained in this study suggest that the interaction of mexiletine with theophylline might be due to competitive inhibition of CYP1A2.Keywords: cytochrome P450, CYP2D6, bufuralol, ethoxyresorufin, furafylline, cDNAexpressed microsomes, relative activity factor These metabolites have no significant antiarrhythmic activity Introduction [5]. Several in vitro [6,7] and in vivo studies [8,9] have suggested that p-and 2-hydroxymexiletine formation are Mexiletine is a class 1B antiarrhythmic agent used for the control of ventricular arrhythmias. It is of particular value mediated by CYP2D6 in humans. Mexiletine is occasionally used together with theophylline because of its long time course of action and its suitability for either parenteral or oral administration [1]. Numerous in patients who have both cardiac and pulmonary diseases. Recent reports have suggested that mexiletine increases the studies have shown that there is marked interindividual variability in mexiletine plasma concentrations after a given theophylline plasma concentration resulting in theophylline dose. As the antiarrhythmic activity and toxicity of mexiletine is strongly correlated with its plasma concentration and as the therapeutic index is narrow [2], monitoring of the plasma concentration is desirable to ensure efficacy and to reduce the side effects of the drug. Mexiletine is eliminated by both renal excretion of the unchanged compound and extensive hepatic metabolism [1, 3]. Less than 10% of mexiletine is recovered unchan...

The inhibitory effects of four selective serotonin reuptake inhibitors (SSRIs), fluoxetine, sertraline, paroxetine and citalopram, and three metabolites (norfluoxetine, demethylcitalopram and didemethylcitalopram), on S-mephenytoin 4'-hydroxylation activities in human liver microsomes were studied. The 4'-hydroxylation of S-mephenytoin, a representative substrate toward CYP2C19, was competitively inhibited by all the SSRIs and their metabolites studied. The mean Ki values of fluoxetine, norfluoxetine, sertraline, paroxetine, citalopram, demethylcitalopram and didemethylcitalopram were 5.2, 1.1, 2.0, 7.5, 87.3, 55.8 and 7.7 gIM, respectively. The findings suggest that some SSRIs and their metabolites with a low Ki value (e.g., fluoxetine, norfluoxetine) may reduce the clearance of drugs metabolized by this isoform of P450, thereby resulting in a possible drug-drug interaction, when administered simultaneously. In addition, SSRIs and their metabolites examined herein may be substrates toward CYP2C19.

ML)SlydUL-I IIC I IICC:IS UI dUUlU lL'+-, -+0 UI /L-IIF) VVdLCI UtPllvduUll Ull the Ulb position kinetics of trimethadione (TMO) and its only metabolite, dimethadione (DMO), and on the microsomal hepatic drug-oxidizing enzyme activities were investigated in male rats. The DMO/TMO ratios in the serum at 2 hr after intra venous administration of 100 mg/kg TMO were significantly decreased in 48 and 72-hr water-deprived rats, but in 24-hr water-deprived rats, the DMO/TMO ratios were not changed as compared to controls and food restrictions.In the 48 and 72-hr water-deprived rats, contents of cytochrome p-450 and activities of amino pyrine N-demethylase were significantly decreased. On the other hand, activities of aniline hydroxylase in these rats were significantly increased as compared to controls and food restrictions.These results suggest that the effects of water deprivation on drug metabolism not only depend on the time of water deprivation but also vary with the indicator substrate.