Nobuo Inotsume

The Inhibitory Effect of Probenecid on Renal Excretion of Famotidine in Young, Healthy Volunteers

Effects of coadministration of probenecid on pharmacokinetic behaviors of famotidine, an H2‐receptor antagonist, after oral administration, were studied in eight young, healthy volunteers. They received an oral 20 mg dose of famotidine with and without coadministration of oral 1500 mg doses of probenecid. The mean area under the serum famotidine concentration‐time curve up to 10 hours was increased by coadministration of probenecid from 424 ±19 (SEM) to 76B ± 39 ng·hr/ml. The mean urinary excretion rate of unchanged famotidine, the mean amount of unchanged famotidine excreted in urine up to 24 hours and mean renal clearance were decreased by coadministration of probenecid. The mean tubular secretion clearance of famotidine was decreased from 196.2 ± 21.4 to 22.0 ± 4.2 ml/min. These data suggest that probenecid, which is a classical inhibitor of renal tubular secretion of organic anions, inhibits the renal tubular secretion of famotidine, which exists partly in a cationic form under physiological pH conditions.

The pharmacokinetics of morphine and its glucuronide conjugate in a rat model of streptozotocin‐induced diabetes and the expression of MRP2, MRP3 and UGT2B1 in the liver

Objectives The aim was to investigate the pharmacokinetics of morphine and its metabolite, morphine‐3‐glucuronide (M3G), in a rat model of streptozotocin (STZ)‐induced diabetes.

Effects of H1-receptor stimulation on coronary arterial diameter and coronary hemodynamics in humans.

Effects of H1-receptor stimulation on coronary arterial diameter and coronary hemodynamics were examined in 11 patients with angiographically normal coronary arteries and without variant angina or resting angina. Selective H1-receptor stimulation was achieved by infusing histamine into the left coronary artery at a rate of 2.0 micrograms/min for 5 minutes after pretreatment with cimetidine (25 mg/kg). Plasma histamine concentration in the coronary sinus, coronary sinus blood flow, heart rate, and aortic pressure were measured before, during, and after the histamine infusion. Coronary arterial diameter was measured by cinevideodensitometric analysis of coronary arteriograms performed before and immediately after the histamine infusion. During the histamine infusion, plasma histamine concentration in the coronary sinus increased from 0.33 +/- 0.06 to 5.86 +/- 0.71 ng/ml (p less than 0.01); coronary sinus blood flow increased from 98 +/- 12 to 124 +/- 13 ml/min (p less than 0.01), and coronary vascular resistance decreased from 1,113 +/- 117 to 851 +/- 91 mm Hg.min/l (p less than 0.01). Heart rate and aortic pressure remained unchanged. The mean luminal diameters of the proximal, middle, and distal left anterior descending artery increased by 9.4 +/- 3.6% (p less than 0.05), 19.2 +/- 3.8% (p less than 0.001), and 31.5 +/- 5.6% (p less than 0.001), respectively, after the histamine infusion. The mean luminal diameters of the proximal, middle, and distal left circumflex artery increased by 15.2 +/- 3.6% (p less than 0.01), 17.5 +/- 5.2% (p less than 0.01), and 20.6 +/- 4.3% (p less than 0.001), respectively, after the histamine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of absorption rate on pharmacokinetics of ibuprofen in relation to chiral inversion in humans

The effect of absorption rate on the pharmacokinetics of ibuprofen enantiomers was investigated in 12 healthy Han Chinese male volunteers following oral administration of immediate‐release (IR) and sustained‐release (SR) preparations containing racemic ibuprofen (rac‐ibuprofen). The area under the curve of the plasma concentration‐time curve (AUC; (mean ± s.d.) values for rac‐ibuprofen were 192.90 ± 43.47 for the SR preparation and 195.90 ± 31.69 μg h mL−1 for the IR preparation. AUC values for the enantiomers after administration of the SR formulation were 55.38 ± 17.79 and 92.51 ± 30.68 μg h mL−1 for R‐ and S‐ibuprofen, respectively, and were 65.94 ± 20.06 and 100.81 ± 32.28 μg h mL−1 for R‐ and S‐ibuprofen after administration of the IR preparation. These values did not differ significantly. Cmax values were significantly decreased with the SR preparation: 25.11 ± 5.71, 12.24 ± 3.79 and 12.38 ± 3.55 μg mL−1 for rac‐, R‐, and S‐ibuprofen, respectively, after administration of the SR preparation, vs 46.21 ± 8.20, 20.82 ± 5.90 and 23.46 ± 7.30 μg mL−1 for rac‐, R‐, and S‐ibuprofen, respectively, after administration of the IR preparation. Mean residence time was significantly increased: 7.01 ± 1.29, 5.52 ± 1.25 and 7.04 ± 1.30 h for rac‐, R‐, and S‐ibuprofen, respectively, after administration of the SR preparation vs 4.34 ± 0.89, 3.43 ± 0.64 and 4.51 ± 0.79 h for rac‐, R‐, and S‐ibuprofen, respectively, after administration of the IR preparation. AUC values for S‐ibuprofen were significantly larger than those for R‐ibuprofen in both preparations, indicating unidirectional chiral inversion. The S/R ratio of serum concentrations of enantiomers was 1.78‐fold higher at 6 h after administration of the SR preparation compared with the IR preparation (P < 0.01).

Determination of (+)- and (−)-nicardipine concentrations in human serum and their correlation with the antihypertensive effect after oral administration of racemic nicardipine

Serum (+)- and (-)-nicardipine concentrations were determined after oral administration of racemic nicardipine, and the relationship between the concentration of each enantiomer and the percentage change in blood pressure was investigated. Serum concentrations of (+)-and (-)-nicardipine were assayed separately by a method combining high-performance liquid chromatography (HPLC) with gas chromatography — mass spectrometry (GS-MS). Linear relationships were found with serum concentrations of 0.25–80 mg·ml−1 for both enantiomers of nicardipine with correlation coefficients of greater than 0.999. A single oral dose of 40 mg racemic nicardipine was given to 15 patients with essential hypertension. Serum (+)-nicardipine concentration was 2–3 times higher than the concentration of (-)-nicardipine 1, 2, and 3 after drug administration. The logarithmically transformed value of the serum (+)-nicardipine concentration was inversely correlated with the percentage change in systolic blood pressure, the correlation being statistically significant 1 and 2 h after drug administration, and also inversely correlated with the percentage change in diastolic blood pressure 1, 2 and 3 h after drug administration. However, the logarithmically transformed value of serum (-)-nicardipine showed no significant correlations with the percentage change in either systolic or diastolic blood pressure.

Determination of sultopride and tiapride in serum by gas chromatography using a surface ionisation detector

A sensitive and selective method has been developed for the determination of sultopride and tiapride in serum using gas chromatography with a surface ionisation detector. No interfering peaks from endogenous substances were observed. The method showed good reproducibility and accuracy, and the standard curve was linear up to 2 micrograms/ml with a correlation coefficient of 0.999. This method is applicable to pharmacokinetic studies and therapeutic drug monitoring of sultopride and tiapride.

Physiologic and Metabolic Aspects of Anticonvulsants

A great number of anticonvulsants are available for treating these different types of epilepsy. Therapeutic drug monitoring has been favored as the method for controlling drug concentrations in the plasma and preventing untoward effects. When these anticonvulsants are prescribed to treat epilepsy in children, careful monitoring is most important because drug metabolism varies depending on maturation and development of body functions. Molecular approaches are also important to elucidate the effectiveness of the drugs for treatment of different seizure disorders and should contribute to a better understanding of body functions.

Effects of insulin on CYP3A activity and nicardipine disposition in streptozotocin-induced diabetic rats.

Objectives  The aim of the study was to clarify the effect of insulin treatment on drug metabolism and disposition.

Altered expression of MRP2, MRP3 and UGT2B1 in the liver affects the disposition of morphine and its glucuronide conjugate in a rat model of cholestasis

Objectives The aim was to investigate the disposition of morphine and morphine‐3‐glucuronide (M3G) in a rat model of cholestasis induced by bile duct ligation (BDL).

Effect of activated charcoal and atropine on absorption and/or exsorption of organophosphorus compounds in rats

Effects of activated charcoal and atropine for the removal of organophosphorus compounds, which remain in the gastrointestinal tract or have already been absorbed into the systemic circulation, were investigated in rats.