Norio Igarashi

Influence of CYP2D6 genotype on metoprolol plasma concentration and beta-adrenergic inhibition during long-term treatment: a comparison with bisoprolol.

In patients routinely treated with metoprolol, influences of CYP2D6 genotype on the response of heart rate to isoproterenol (IP) were studied at its peak and trough concentrations and were compared with those of bisoprolol. In 72 patients treated with metoprolol or bisoprolol, CYP2D6 genotype (ie, CYP2D6*1, *2, *4, *5, *10, and *14) was determined. No patients except one who was heterozygous for CYP2D6*5 carried the null alleles of CYP2D6. The homozygote frequency for CYP2D6*10 was relatively high (19.4%) and these patients had greater peak and trough plasma concentrations of metoprolol than the other patients. Isoproterenol-induced percentage increases in heart rate were 58% and 38% less at the low and high rate of isoproterenol infusion (0.02 and 0.04 μg/kg/min), respectively, in patients homozygous for CYP2D6*10 than in the other patients at the trough, but not at the peak concentrations. In contrast, CYP2D6 genotype did not affect plasma concentrations of bisoprolol and the extent of its β-adrenergic inhibition. Thus, in patients routinely treated with metoprolol, CYP2D6 genotype significantly affects circadian variations of β-adrenergic inhibition induced by metoprolol. In contrast, bisoprolol has a relatively constant β-adrenergic inhibition independent of CYP2D6 genotype.

Ischemic preconditioning accelerates the fatty acid oxidation of rat hearts.

BACKGROUND Ischemic preconditioning (IPC) reduced myocardial ATP depletion during sustained ischemia and has a powerful protective effect on the myocardium. The purpose of the present study was to clarify the effects of IPC on myocardial accumulation of fatty acid (FA) tracer and its intracellular metabolism. METHODS Myocardial ischemia-reperfusion (MI-R) injury was induced by the left coronary artery ligation for 15 min followed by reperfusion in Wistar rats. IPC was achieved with a single cycle of 5-minute coronary ligation followed by 5-minute reperfusion before MI-R. Three days after ischemia-reperfusion, FA metabolism was evaluated in rats with or without IPC using (131)I- and (125)I-15-(p-iodophenyl)-9-methylpentadecanoic acid (9MPA) and thin-layer chromatography. RESULTS IPC attenuated a reduction of 9MPA accumulation in ischemic region (IR). The metabolite fraction of 9MPA including both early and late metabolites was less in IR as compared to non-IR in rats without IPC. IPC increased the final metabolic product of 9MPA processed via alpha- and beta-oxidation in both IR and non-IR. CONCLUSIONS IPC accelerated fatty acid oxidation in both IR and non-IR. This alteration in fatty acid metabolism would inhibit an intracellular accumulation of detrimental fatty acid metabolites.