Flecainide-induced QRS prolongation did not differ between the new controlled-release form and the immediate-release form. Flecainide plasma concentrations associated with the new controlled-release form predicted QRS prolongation with less variability compared with the immediate-release form. The CYP2D6 polymorphism did not appear to influence flecainide disposition kinetics or electrocardiographic effects at steady state.

An altered pattern of cytochrome P-450-dependent microsomal steroid metabolism was identified in female mouse liver tumors induced by 5,9-dimethyldibenzo[c,g]carbazole, a potent organo-specific liver carcinogen. These tumor tissues were compared to extratumoral liver parenchyme, to normal, fetal and neonatal livers and to spontaneous liver tumors, the frequency of which is very low in the highly hybridized mouse strain (XVIInc/Z) used for liver tumorigenesis. Cytochrome P-450-dependent steroid hydroxylase activities were measured by the identification and quantification of four monohydroxyprogesterone and eight monohydroxytestosterone metabolites. In contrast to a general decrease (50%) of total P-450 in tumor microsomes, the individual steroid hydroxylases were regulated differently. Progesterone 16 alpha- and testosterone 6 alpha-, 6 beta-, 7 alpha- and 16 alpha-hydroxylase activities were decreased 50%, and more, whereas progesterone and testosterone 15 alpha-hydroxylase activities were raised 3-4 times with regard to microsomal protein content and 6-7 times with regard to total P-450. Consequently the most prominent feature of the steroid metabolism by tumor-borne microsomes is the hydroxylation at the 15 alpha-position. Furthermore, minor testosterone 2- and 15 beta-hydroxylase activities showed equally an increase of approximately 4 times (8 times with regard to total P-450). The observed new tumoral pattern of P-450-dependent microsomal steroid metabolism appearing characteristically in spontaneous and chemically induced liver tumors indicates that particular P-450 enzymes are strongly expressed in mouse liver tumors. These enzymes may be used as markers for early stages in liver tumorigenesis.