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1 Cilostazol (OPC-13013) undergoes extensive hepatic metabolism. The hydroxylation of the quinone moiety of cilostazol to OPC-13326 was the predominant route in all the liver preparations studies. The hydroxylatioin of the hexane moiety to OPC-13217 was the second most predominant route in vitro. 2 Ketoconazole (1 µM) was the most potent inhibitor of both quinone and hexane hydroxylation. Both the CYP2D6 inhibitor quinidine (0.1 µM) and the CYP2C19 inhibitor omeprazole (10 µM) failed to consistently inhibit metabolism of cilostazol via either of these two predominant routes. 3 Data obtained from a bank of pre-characterized human liver microsomes demonstrated a stronger correlation (r²=0.68, P<0.01) between metabolism of cilostazol to OPC-13326 and metabolism of felodipine, a CYP3A probe, that with probes for any other isoform. Cimetidine demonstrated concentration-dependent competitive inhibition of the metabolism of cilostazol by both routes. 4 Kinetic data demonstrated a Km value of 101 µM for cilostazol, suggesting a relatively low affinity of cilostazol for CYP3A. While recombinant CYP1A2, CYP2D6 and CYP2C19 were also able to catalyze formation of specific cilostazol metabolites, they did not appear to contribute significantly to cilostazol metabolism in whole human liver microsomes. Human & Experimental Toxicology (2000) 19, 178–184. [ABSTRACT FROM AUTHOR]

1. The stereoselective S-oxidation and reduction pathways of flosequinan [(+/-)-7- fluoro-1-methyl-3-methylsulphinyl-4-quinolone] in rat were investigated in vitro. 2. Cytosol from both the liver and kidney catalysed the reduction of R(+)-flosequinan (R-FSO) and S(-)-flosequinan (S-FSO) to flosequinan sulphide (FS, 7-fluoro-1-methyl3- methylthio-4-quinolone). Flosequinan sulphone (FSO2, 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone) was not reduced to R-FSO or S-FSO. 3. Liver microsomes catalysed four different S-oxidation pathways in the presence of NADPH, namely oxidation of FS to R-FSO and S-FSO and from R-FSO and S-FSO to FSO2. The formation of R-FSO and S-FSO from FS each exhibited a biphasic kinetic pattern, indicating that at least two distinct enzymes were involved. The pathway from FS to R-FSO appeared mainly catalysed by flavin-containing monooxygenases (FMO). 4. S-oxidation of FS to R-FSO was more rapid than that of FS to S-FSO. S-oxidation of FS to either R-FSO or S-FSO in liver microsomes was more rapid than that of either RFSO or S-FSO to FSO2. 5. Microsomes from both the kidney and lung catalysed the stereoselective S-oxidation of FS to R-FSO, and FMO was likely to have participated in these reactions. [ABSTRACT FROM AUTHOR]

1. The biotransformation of 1-(3,4-dichlorobenzyl)-5-octylbiguanide (OPB-2045), a new potent biguanide antiseptic, was investigated in male beagle dogs. Urinary and faecal excretion of unchanged compound and metabolites were studied following a single subcutaneous injection of C-labeled compound at a dose of 1 mg kg. 2. Four urinary metabolites were structually identified using synthetic standards and orspectraldataas3,4-dichlorobenzoicacid,6-\[5-(3,4-dichlorobenzyl)-1-biguanidino hexanoic acid (DM-210), 4-\[5-(3,4-dichlorobenzyl)-1-biguanidino] butanoic acid (DM212) and 5-\[5-(3,4-dichlorobenzyl)-1-biguanidino] pentanoic acid (DM-213). 3. The predominant radioactive substances in the excreta were DM-213 and DM-210 at 26 1% and 25 5%, respectively, of the dose. No unchanged compound was detected in the urine, and in the faeces it was only 2% of the dose. [ABSTRACT FROM AUTHOR]

1. The metabolism of carteolol, a beta-adrenoceptor blocking drug, was investigated in male Sprague- Dawley rat liver microsomes. 2. The formation of 8-hydroxycarteolo l was the principal metabolic pathway of carteolol in vitro and followed Michaelis-Mente n kinetics with a Km=11.0 +/- 5. 4 muM and a Vmax=1.58 +/- 0.64 nmol/min/nmol P450 respectively (mean+/- SD, n = 5). Eadie-Hofstee plot analysis of carteolol 8-hydroxylase activity confirmed single-enzyme MichaelisMenten kinetics. 3. The cytochrome P450 isoforms involved in 8-hydroxylation of carteolol were investigated using selective chemical inhibitors and polyclonal anti-P450 antibodies. Quinine ( Ki = 0.06 muM ) and quinidine ( Ki=2.0 muM), selective inhibitors of CYP2D1, competitively inhibited 8-hydroxycarteolo l formation. Furthermore, only anti-human CYP2D6 antibody inhibited this reaction. 4. These results suggest that carteolol is metabolized to 8-hydroxycarteolo l by CYP2D1.The Km of carteolol for CYP2D1 in male rat liver microsomes was much greater than those of propranolol or bunitrolol, indicating that carteolol has a lower affinity for CYP2D1 compared with these other beta-adrenoceptor blocking drugs. [ABSTRACT FROM AUTHOR]

Objective: The present study was conducted to identify in vitro the cytochrome P450(CYP) isoform involved in the metabolic conversion of reduced haloperidol to haloperidol using microsomes derived from human AHH-1 TK +/− cells expressing human cytochrome P450s. The inhibitory and/or stimulatory effects of reduced haloperidol or haloperidol on CYP2D6-catalyzed carteolol 8-hydroxylase activity were also investigated. Results: The CYP isoform involved in the oxidation of reduced haloperidol to haloperidol was CYP3A4. CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 2E1 were not involved in the oxidation. The kM value for the CYP3A4 expressed in the cells was 69.7 μmol · l−1, and the Vmax was 4.87 pmol · min−1 · pmol−1 P450. Troleandomycin, a relatively selective probe for CYP3A enzymes, inhibited the CYP3A4-mediated oxidation of reduced haloperidol in a dose-dependent manner. Quinidine and sparteine competitively inhibited the oxidative reaction with a ki value of 24.9 and 1390 μmol · l−1, respectively. Carteolol 8-hydroxylase activity, which is a selective reaction probe for CYP2D6 activity, was inhibited by reduced haloperidol with a ki value of 4.3 μmol · l−1. Haloperidol stimulated the CYP2D6-mediated carteolol 8-hydroxylase activity with an optimum concentration of 1 μmol · l−1, whereas higher concentrations of the compound (>10 μmol · l−1) inhibited the hydroxylase activity. Conclusion: It was concluded that CYP3A4, not CYP2D6, is the principal isoform of cytochrome P450 involved in the metabolic conversion of reduced haloperidol to haloperidol. It was further found that reduced haloperidol is a substrate of CYP3A4 and an inhibitor of CYP2D6, and that haloperidol has both stimulatory and inhibitory effects on CYP2D6 activity. [ABSTRACT FROM AUTHOR]

Objectives: To determine human cytochrome P450 isoform(s) (CYPs) involved in the metabolism of carteolol, the biotransformation of the compound was investigated in vitro using ten isoforms of human cytochrome P450 expressed in human AHH-1 TK ± cell lines. In addition, the inhibitory effects of carteolol on the activities of important CYP isoforms, namely, CYP1A2, 2C9, 2C19, 2E1, and 3A4, were examined. Results: Carteolol was metabolised to 8-hydroxycarteolol by CYP 2D6 with KM and Vmax values of 183 μmoles · l−1 and 26.09 pmol · min−1 · pmol−1 P450, respectively. CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1 and 3A4 were not involved in the metabolism of the compound. CYP2D6-mediated carteolol 8-hydroxylase activity was inhibited by quinidine, propranolol, nortriptyline, dextromethorphan, sparteine, bufuralol, and biperiden. Biperiden competitively inhibited the catalytic reaction with a Ki value of 0.45 μmoles · l−1. Carteolol did not affect the following catalytic reactions:␣CYP1A2-mediated ( R)-warfarin 6-hydroxylation, CYP2C9-mediated tolbutamide methylhydroxylation, CYP2C19-mediated ( S)-mephenytoin 4-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, and CYP3A4-mediated testosterone 6β-hydroxylation. Conclusion: 8-Hydroxylation is the only cytochrome P450-catalyzed metabolic reaction of carteolol by its expressed microsomes, and CYP2D6 is the principal isoform of the enzyme involved in the catalytic reaction. Carteolol has neither stimulative nor inhibitory effects on CYP1A2, 2C9, 2C19, 2E1, and 3A4 activities. [ABSTRACT FROM AUTHOR]