Katsuhiko Okumura
Kyoto University
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Featured researches published by Katsuhiko Okumura.
Clinical Pharmacology & Therapeutics | 1983
Ryohei Hori; Katsuhiko Okumura; Akira Kamiya; Hiromi Nihira; Hiroshi Nakano
We analyzed the relationship between functional damage and transport processes in the kidney in patients with glomerulonephritis and renal failure by a new analytic method. In renal failure patients, there was substantial diminution of maximum transport of secretion in renal tubules. This reduction affected the urinary excretion of ampicillin and cephalexin substantially because both drugs depend on active renal tubular secretion. Our results indicate that dosage adjustment based on creatinine clearance is not appropriate for patients receiving drugs requiring active tubular secretion for urinary excretion. Our data point to a need for a prolongation of the dosage interval of cephalexin to 20 times that in normal subjects, while five times is recommended by the creatinine clearance. In these patients, it is therefore suggested that a dosage adjustment method that involves both factors—glomerular and renal tubular functions—is required.
Biochemical and Biophysical Research Communications | 1985
Ryohei Hori; Ken-ichi Inui; Hideyuki Saito; Yasuhisa Matsukawa; Katsuhiko Okumura; Kazuwa Nakao; Narito Morii; Hiroo Imura
The binding of alpha-human atrial natriuretic polypeptide (alpha-hANP) to brush border and basolateral membranes isolated from the rat renal cortex was studied at 0 degree C by a rapid filtration technique. Specific binding of 125I-alpha-hANP to basolateral membranes reached a steady state at 4 hr. The binding to brush border membranes was maximal at 5-15 min and then rapidly decreased. The analysis of incubation mixtures with basolateral membranes revealed little degradation of 125I-alpha-hANP during the 4-hr incubation, while there was extensive degradation of the ligand with brush border membranes during the 30-min incubation. High affinity binding of 125I-alpha-hANP was demonstrated on basolateral membranes but not on brush border membranes. These data suggest that specific receptors for alpha-hANP are localized on basolateral membranes of the renal cortex.
Journal of Pharmacy and Pharmacology | 1984
Ryohei Hori; Katsuhiko Okumura; Ken-ichi Inui; Masato Yasuhara; Kazushi Yamada; Tsunetaro Sakurai; Chuichi Kawai
A high‐performance liquid chromatographic method is described for the simultaneous determination of ajmaline and quinidine in human plasma. With 0·5 ml plasma samples of ajmaline and quinidine, concentrations as low as 0·001 and 0·01 μg ml−1, respectively, could be detected and the technique could be used to investigate the effect of quinidine on the pharmacokinetics of ajmaline. Four healthy subjects were given oral ajmaline (50 mg) alone or in combination with quinidine sulphate (200 mg) on separate occasions. When ajmaline was administered alone, its plasma concentrations were less than 0·03 μg ml−1. Quinidine induced a marked increase to give a mean peak concentration of ajmaline which increased from 0·018 μg ml−1 after a single administration to 0·141 μg ml−1 in combination with quinidine. The area under the ajmaline concentration‐time curves was increased 10 to 30‐fold by the concurrent administration of quinidine. According to the one compartment open model, the absorption rate constant of ajmaline did not change appreciably, but the elimination rate constant was reduced to approximately 50% of the value in the absence of quinidine. The results indicate the existence of a significant interaction between oral ajmaline and quinidine.
Pharmaceutical Research | 1987
Hisahiro Yoshida; Katsuhiko Okumura; Ryohei Hori
To clarify the mechanism by which basic drugs accumulate in the lung, the binding selectivity of drugs to different subcellular structures of the perfused rat lung was examined. Imipramine, quinine, and metoclopramide were used as examples of basic drugs. The accumulation of basic drugs was highest in the mitochondrial fraction. The drug accumulation in the lung mitochondrial fraction increased with increasing lipid solubility and was dose dependent. These results suggest the presence of specific binding sites for basic drugs in mitochondria and that mitochondria play an important role as a reservoir for basic drugs.
Pharmaceutical Research | 1987
Ryohei Hori; Katsuhiko Okumura; Hisahiro Yoshida
The role of the mitochondria in the accumulation of basic amine drugs in the rat lung was studied. Drug binding to the mitochondria was rapid and reached maximum levels after 2.5 min of incubation. Lipophilic basic drugs accumulated in the mitochondria more than nonlipophilic basic drugs and non-basic drugs, and the accumulation was dose dependent. Schatchard plots revealed at least two independent sets of binding sites for basic drugs in the mitochondria. The binding was competitively inhibited by other basic drugs but not nonbasic drugs. The degree of inhibition by competing basic drugs was correlated with their lipid solubilities. These findings with isolated mitochondria agree with previous results obtained with the perfused lung preparation and indicate that the mitochondria play an important role in the accumulation of basic drugs in the lung.
Clinical Pharmacology & Therapeutics | 1985
Ryohei Hori; Katsuhiko Okumura; Hiromi Nihira; Hiroshi Nakano; Kazuyoshi Akagi; Akira Kamiya
We describe a new method of drug dosage adjustment. The method simultaneously considers glomerular and tubular functions as parameters, because nonparallel decreases in both functions limit the use of the conventional endogenous creatinine clearance (CLCR) method for dosage adjustment. In the new method, CLCR and the 15‐minute phenolsulfonphthalein (PSP15′) test were used and applied to patients with renal insufficiency with cephalexin (CEX) as a model drug for renal tubular secretion. The results clearly demonstrate good control of plasma CEX concentrations by the CLCR‐PSP15′ method, whereas there were marked changes in plasma CEX levels with the CLCR method alone. Our method appears to be more useful for patients with renal impairment than the conventional CLCR method for CEX, which is mainly excreted in urine by renal tubular secretion. A nomogram for the CEX dosing interval is proposed for application to clinical practice.
Biochemical Pharmacology | 1985
Ryohei Hori; Katsuhiko Okumura; Masato Yasuhara; Hirokazu Katayama
The effect of acute renal failure (ARF) on the hepatic uptake and metabolism of propranolol was investigated in relation to the hepatic clearance of the drug. ARF was induced by the subcutaneous injection of uranyl nitrate to rats. The uptake rate of propranolol in the isolated perfused liver was determined by the multiple-indicator dilution method and was found to decrease from 43.6 +/- 2.0 min-1 (mean +/- S.E.) in control to 29.4 +/- 1.7 min-1 in ARF (P less than 0.001). The recovery fraction of propranolol in effluent venous blood increased about twofold in ARF compared to control (P less than 0.05). The metabolic activity for propranolol was examined using the hepatic microsomal fraction prepared from control and ARF rats. There was no significant difference in the kinetics of oxidative metabolism of propranolol between two groups. These results suggest that the previously reported decrease in the hepatic clearance of propranolol in ARF is due to decreased hepatic uptake of the drug from the blood into the liver cells.
Pharmaceutical Research | 1989
Ryohei Hori; Fusao Komada; Seigo Iwakawa; Yutaka Seino; Katsuhiko Okumura
The present study was undertaken to develop an agent that stabilizes insulin injected subcutaneously. 125I-Porcine insulin with 0.2 U/kg unlabeled porcine insulin was subcutaneously injected with or without collagen in the rat under the depilated skin of the back. At various times, the radioactivity in subcutaneous tissue was assayed for insulin and its metabolites by gel filtration. The degradation and absorption rate constants of insulin at the subcutaneous injection site were estimated according to a one-compartment model. The degradation rate constant of insulin in the presence of collagen at the injection site was less than half of the control rate. The inhibition was confirmed by increases in the immunoreactive insulin plasma levels and the hypoglycemic effect in rats and healthy volunteers. We postulate that collagen prevents insulin from being degraded by inhibiting proteolytic enzymes, mainly collagenase-like peptidase, in subcutaneous tissue.
Journal of Pharmacy and Pharmacology | 1972
Shunji Furusawa; Katsuhiko Okumura; Hitoshi Sezaki
The transfer process of various acidic drugs from water into chloroform containing phospholipids has been examined using a nonemulsifying system. The ionized forms of the drugs which have little lipid solubility show a marked increase in transfer to the chloroform phase containing lecithin at the physiological pH of the small intestine. The pH‐profiles of salicylic acid, p‐aminobenzoic acid and sulphisoxazole transfer are in good agreement with available in situ absorption data. These results suggest a role for phospholipids in the intestinal absorption of ionized acidic drugs which has not been clearly apparent with pH‐partition hypothesis alone.
Journal of Pharmacokinetics and Biopharmaceutics | 1987
Masato Yasuhara; Yukiya Hashimoto; Katsuhiko Okumura; Ryohei Hori; Tsunetaro Sakurai; Chuichi Kawai
Pharmacokinetics and pharmacodynamics of ajmaline were studied in four healthy dogs after intravenous administration of the drug at the infusion rate of 1.0 mg/min for 45 min. Ajmaline exhibited a saturable binding to plasma protein. One kind of binding site was found in the range of observed drug concentrations and its binding capacity showed nearly threefold interindividual difference. The time course of ajmaline concentration in whole blood Cbcould be described by the two-compartment open model and the unbound concentration of ajmaline in plasma Pf wasestimated from Cbby using the hematocrit value and the parameters of plasma protein binding and erythrocyte partitioning. The pharmacologic responses to ajmaline were assessed by recording ECG, and the changes in PQ and QRS interval were studied in relation to ajmaline disposition. When ECG changes were related to the ajmaline concentration, a significant degree of hysteresis was observed. The relationship between the unbound drug concentration and the pharmacologic effect was analyzed by a combined pharmacokinetic-pharmacodynamic model, where the hypothetical effect compartment is connected to the Pfin the central compartment by a first-order process. This model allows estimation of the changes in PQ and QRS intervals after intravenous administration of ajmaline. By comparing the drug effect on PQ and QRS intervals, it was suggested that ajmaline distributes to the atrial and the ventricular tissue in a similar degree and causes a reduction in the conduction rate in both sites with similar activity.