Lack of differences in diclofenac (a substrate for CYP2C9) pharmacokinetics in healthy volunteers with respect to the single CYP2C9*3 allele.

OBJECTIVES: Evidence exists to suggest that diclofenac is metabolised by CYP2C9. The present study was undertaken in order to evaluate the effect of the single CYP2C9*3 variant on drug metabolism using diclofenac as a probe drug. METHODS: A single dose of diclofenac was administered orally to 12 healthy subjects in whom the genotype of CYP2C9 had been determined previously. The disposition kinetics of diclofenac were compared between homozygotes for the wild type (CYP2C9*1/*1, n = 6) and heterozygotes for the Leu359 variant (CYP2C9*1/*3, n = 6). RESULTS: For diclofenac, the following kinetic parameters were observed in the CYP2C9*1/*1 and CYP2C9*1/*3 subjects, respectively (mean +/- SD): apparent oral clearance (ml/kg/h) 355.8 +/- 56.9 and 484.4 +/- 155.3; area under plasma concentration time curve (microg h/ml) 2.7 +/- 0.7 and 1.9 +/- 0.6. The formation clearance of 4'-hydroxydiclofenac (ml/kg/h) was 63.6 +/- 19.1 in the CYP2C9*1/*1 subjects compared with 75.9 +/- 27.6 in the CYP2C9*1/*3 subjects. There were no significant differences in any of the kinetic parameters for either diclofenac disposition or formation clearance of 4'-hydroxydiclofenac between the two genotype groups. CONCLUSION: Since the disposition kinetics of diclofenac does not change in subjects with the single CYP2C9*3 mutant allele, it is suggested that the effects of CYP2C9 polymorphisms on the drug metabolism tend to be substrate specific.

The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics.

PURPOSE: The aim of this study was to clarify the effects of genetic polymorphisms of cytochrome P450 (CYP) 2C9 and 2C19 on the metabolism of phenytoin (PHT). In addition, a population pharmacokinetic analysis was performed. METHODS: The genotype of CYP2C9 (Arg144/Cys, Ile359/Leu) and CYP2C19(*1, *2 or *3) in 134 Japanese adult patients with epilepsy treated with PHT were determined, and their serum concentrations of 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) enantiomers, being major metabolites of PHT, were measured. A population pharmacokinetic analysis (NONMEM analysis) was performed to evaluate whether genetic polymorphism of CYP2C9/19 affects the clinical use of PHT by using the 336 dose-serum concentration data. RESULTS: The mean maximal elimination rate (Vmax) was 42% lower in the heterozygote for Leu359 allele in CYP2C9, and the mean Michaelis-Menten constants (Km) in the heterozygous extensive metabolizers and the poor metabolizers of CYP2C19 were 22 and 54%, respectively, higher than those without the mutations in CYP2C9/19 genes. (R)- and (S)-p-HPPH/PHT ratios were lower in patients with mutations in CYP2C9 or CYP2C19 gene than those in patients without mutations. CONCLUSIONS: Although the hydroxylation capacity of PHT was impaired with mutations of CYP2C9/19, the impairment was greater for CYP2C9. In view of the clinical use of PHT, two important conclusions were derived from this population study. First, the serum PHT concentration in patients with the Leu359 allele in CYP2C9 would increase dramatically even at lower daily doses. Second, the patients with CYP2C19 mutations should be treated carefully at higher daily doses of PHT.

[A comparison of the effects of the beta-adrenergic blockers, carteolol (OPC-1085), propranolol and alprenolol on isolated rat cardiac muscles (author's transl)].

The effects of carteolol, propranolol and alprenolol were studied by using spontaneously contracting atria, atrial muscle and papillary muscle prepared from rat hearts. Propranolol, alprenolol and carteolol caused decreases in atrial rate and in contractile tension of electrically driven cardiac muscles in concentrations of 10(-6) to 10(-5) g/ml, 10(-6) to 10(-5) g/ml and 10(-4) g/ml, respectively. These compounds, also, effectively prevented electrically-induced atrial arrhythmias in these concentrations. Contractile tension of the cardiac muscles was increased by carteolol in concentrations of 10(-7) to 10(-6) g/ml. The refractory period of the cardiac muscles was prolonged in the presence of alprenolol (10(-7) to 10(-6) g/ml) or carteolol (10(-6) to 10(-5) g/ml). The refractory period of the papillary muscle was increased by 10(-7) to 10(-6) g/ml of propranolol. The maximum driven frequency (MDF) of the atrial muscle was reduced by 5X10(-8) to 10(-7) g/ml of carteolol or by 5X10(-8) g/ml of alprenolol, and MDF of the papillary muscle by 5X10(-7) g/ml of propranolol. In extremely high concentrations, these compounds significantly reduced MDF of the cardiac muscle. These results suggest that the antiarrhythmic action of alprenolol and carteolol is more predominant in atria than in ventricles, whereas the reverse is true for propranolol.