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This study was conducted to examine the involvement of cytochrome P450 (CYP450) and the flavin-containing monooxygenase (FMO) in the sulphoxidation of ethyl methyl sulphide (EMS), 4-chlorophenyl methyl sulphide (CPMS) and diphenyl sulphide (DPS) in human liver microsomes from a phenotypic CYP2D6 extensive metabolizer. Human liver microsomes catalyzed the sulphoxidation of EMS, CPMS and DPS to their corresponding sulphoxides. Lineweaver-Burk plots for the sulphoxidation of EMS in human liver microsomes indicated that the apparent Km and Vmax were 1.53 ± 0.07 mM and 1.11 ± 0.25 nmoles/mg protein/min, respectively. The apparent Km and Vmax for the sulphoxidation of CPMS were 0.17 ± 0.05 mM and 1.41 ± 0.16 nmoles/mg protein/min, respectively. The apparent Km and Vmax for the sulphoxidation of DPS were 0.10 ± 0.01 mM and 1.08 ± 0.05 nmoles/mg protein/min, respectively. Methimazole noncompetitively inhibited the sulphoxidation of EMS, CPMS and DPS by human liver microsomes with Ki values of 8.6 ± 0.6, 5.7 ± 0.4 and 6.6 ± 0.5 mM, respectively. SKF525A noncompetitively inhibited the sulphoxidation of CPMS and DPS by human liver microsomes with Ki values of 6.6 ± 0.4 and 0.40 ± 0.1 mM, respectively. The results suggest that FMO is involved in the sulphoxidation of EMS, CPMS and DPS while CYP450 is involved in the sulphoxidation of CPMS and DPS in human liver microsomes. [Copyright &y& Elsevier]

Abstract: A facile preparation of azolyl steroids, VN/85-1 and VN/87-1 (potent inhibitors of CYP17) has been developed. This process without tedious chromatographic separations improved the overall yields from 55 and 45% to 70 and 65% for VN/85-1 and VN/87-1, respectively. Pharmacokinetic studies of VN/85-1 were conducted in male SCID mice. Following subcutaneous (s.c.) administration of 100mg/kg of VN/85-1, peak plasma level of 16.73μg/ml occurred after 45min, and the compound was cleared rapidly with a t1/2 of 52.34min. The bioavailability of VN/85-1 after s.c. administration was 83.0%. VN/85-1 was also rapidly metabolized to the corresponding 3-oxo-4-ene analog, 17-(1H-imidazol-1-yl)androsta-4,16-diene-3-one (VN/108-1). In our attempt to optimize the anti-tumor efficacy of these two CYP17 inhibitors, we studied their anti-tumor efficacies in male SCID mice bearing LNCaP tumor xenografts, utilizing various drug doses and drug scheduling. Three times a day dose regimen (3× dose regimen) of VN/85-1 was more effective than a once daily dose. In contrast, 3× dose regimen doses of VN/87-1 were less effective than the once daily dose. However, at their effective dosage regimes, VN/85-1 and VN/87-1 were each as effective as castration and more effective than finasteride or casodex, an anti-androgen used for prostate cancer (PC) therapy. For all of the treatments, there was a strong correlation between the tumor volumes and other associated parameters, such as, tumor weights, and serum testosterone (T) and PSA levels. These results indicate that VN/85-1 or VN/87-1 may be useful in the treatment of hormone-dependent prostate cancer. [Copyright &y& Elsevier]