This study was performed to estimate the mean pharmacokinetic parameters of routinely administered metoprolol in middle-aged and elderly Japanese patients. Whole blood concentration data (65 samples) at steady-state following repetitive administration to 34 patients were analyzed using a nonlinear mixed effects model. A one-compartment model was parameterized in terms of oral clearance (CL/F) and apparent volume of distribution (V/F). We evaluated the effect of polymorphic alleles (CYP2D6*2, CYP2D6*10, CYP2C19*2 and CYP2C19*3), age, gender, and heart failure on the pharmacokinetic parameters of metoprolol. The CL/F value in patients homozygous for the CYP2D6*10 allele was 64% lower than that in patients with a CYP2D6*1/*1 or *1/*2 genotype. The CL/F value in older (Ͼ70 years old) patients was 26% lower than that in younger (Յ70 years old) patients. In addition, the V/F value in patients homozygous for the CYP2D6*10 allele was 25% lower than that in patients with the CYP2D6*1/*1 or *1/*2 genotype. On the other hand, the CYP2C19 genotype, gender, and heart failure showed no significant effects on the pharmacokinetics of metoprolol. The results suggest that the pharmacokinetic variability of metoprolol in Japanese extensive metabolizers of CYP2D6 is very large, probably because CYP2D6*10 is responsible not only for the decreased systemic clearance (CL) but also for the increased bioavailability (F) of the drug.

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 microg/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 beta-adrenergic inhibition. Thus, in patients routinely treated with metoprolol, CYP2D6 genotype significantly affects circadian variations of beta-adrenergic inhibition induced by metoprolol. In contrast, bisoprolol has a relatively constant beta-adrenergic inhibition independent of CYP2D6 genotype.

To characterize the membrane transport responsible for the renal excretion and intestinal absorption of levofloxacin, we performed pharmacokinetic analysis of transcellular transport across LLC-PK 1 and Caco-2 cell monolayers. Transcellular transport of levofloxacin in LLC-PK 1 cells was greater in the basolateral-to-apical direction than in the opposite direction. Pharmacokinetic analysis indicated that basolateral uptake was the direction-determining step for the transcellular transport of levofloxacin in LLC-PK 1 cells. The apical efflux clearance of levofloxacin in LLC-PK 1 cells was increased at the medium pH 6 as compared with at pH 8, suggesting that membrane transport characteristics of levofloxacin are apparently similar to those of a prototypical organic cation, tetraethylammonium. On the other hand, transcellular transport of levofloxacin in Caco-2 cells was only slightly greater in the basolateral-to-apical direction than in the opposite direction. The apical efflux clearance of levofloxacin in Caco-2 cells was greater than basolateral efflux clearance, and apical influx clearance was greater than any other membrane transport clearance. In addition, the apical uptake of levofloxacin as well as quinidine in Caco-2 cells was inhibited significantly by nicotine and imipramine. The findings indicated that some transporters are responsible not only for the efflux but also for the influx of levofloxacin at the apical membrane of Caco-2 cells.

Bisoprolol is a selective b 1 -blocker without intrinsic sympathomimetic activity, 1) and has been used widely in patients with cardiovascular diseases such as hypertension, angina pectoris, and cardiac arrhythmias in Japan. In healthy young subjects, 50% of the total dose of bisoprolol is metabolized in the liver, while 50% is excreted via the kidneys unchanged.2) The pharmacokinetics of bisoprolol shows less interindividual variability than that of other b-blockers because of a nearly complete absorption, small hepatic first-pass metabolism, and balanced renal excretion. [3][4][5] In elderly patients, however, the age-associated decline in glomerular filtration and renal tubular secretion can affect the elimination of a drug dependent on the kidney for excretion. 6) In addition, hepatic drug metabolism may be diminished due to decreases in hepatic blood flow, liver mass, and levels of cytochrome P450 (CYP) drug-metabolizing enzymes. 7,8) However, the pharmacokinetics of bisoprolol has not been clarified in routinely treated elderly Japanese patients.The present study was designed to evaluate the pharmacokinetic variability of routinely administered bisoprolol in middle-aged and elderly Japanese patients. A pharmacokinetic analysis was performed using a nonlinear mixed effects model (NONMEM). In addition, it is reported that drug metabolizing activity is often genetically polymorphic. 9) In this study, therefore, we also evaluated the effects of well-known genetic polymorphisms of CYP2D6 and CYP2C19 on the pharmacokinetic variability of bisoprolol. MATERIALS AND METHODS Subjects and Study ProtocolsThe subjects were 29 male and 11 female Japanese patients aged between 43 and 89 (meanϮS.D.: 63.5Ϯ10.1) years old, and mean body weight (ϮS.D.) was 63.8Ϯ10.7 kg. In this study, seven patients were characterized as having New York Heart Association (NYHA) class II congestive heart failure (CHF), but no patients had severe cardiac, hepatic, or renal failure. That is, mean (ϮS.D.) values of serum creatinine concentration, glutamic oxaloacetic transaminase activity, and glutamic pyruvic transaminase activity in the patients were 0.82Ϯ0.19 mg/dl (range: 0.50-1.30 mg/dl), 26Ϯ11 IU/l (range: 9-65 IU/l), and 29Ϯ26 IU/l (range: 4-160 IU/l), respectively. All patients had been routinely treated with an oral administration of bisoprolol hemifumarate (Maintate ® Tablets, Tanabe Pharmaceutical Co., Osaka, Japan) at doses of 2.5 or 5 mg/d, and the drug was administered once a day in all patients. No patients had received any potent inhibitor of CYP2D6 (e.g. amiodarone and quinidine) concomitantly. The total number of blood samples obtained at steady-state following repetitive administration was 94. That is, one or two blood samples for all 40 patients were obtained between 2.3 and 7.0 h after the administration. Additional blood samples just before administration were obtained in 36 patients. All patients (11 inpatients and 29 outpatients) gave written consent to participate in this study, which was approved by the ethics committee...

The aim of this study was to investigate the involvement of the peptide transporter for absorption of levofloxacin in Caco-2 cells. To evaluate the activity of apical and basolateral peptide transport, we first performed pharmacokinetic analysis of transcellular transport of glycylsarcosine (Gly-Sar) in cell monolayers grown on porous membrane filters. Transcellular transport of Gly-Sar at the medium pH 6 was greater in the apical-to-basolateral direction than in the opposite direction. Influx clearance of Gly-Sar at the apical membrane was much greater than basolateral influx and efflux clearance, indicating that the apical peptide transporter plays an important role in directional transcellular transport of the dipeptide across Caco-2 cell monolayers. We then evaluated the effect of various compounds on the uptake of Gly-Sar and levofloxacin at the apical membrane of Caco-2 cells. The apical uptake of [3H]Gly-Sar was significantly inhibited by Ala-Ala, Gly-Sar, and also levofloxacin, whereas that of [14C]levofloxacin was not inhibited by Ala-Ala and Gly-Sar. On the other hand, the apical uptake of [14C]levofloxacin was inhibited by nicotine, enalapril, fexofenadine, and L-carnitine. These findings indicated that the apical uptake transporter of levofloxacin is distinct from the peptide transporter in Caco-2 cells.