Shinichiro Nishio

Interaction between Amlodipine and Simvastatin in Patients with Hypercholesterolemia and Hypertension

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are often prescribed in association with antihypertensive agents, including calcium antagonists. Simvastatin is an HMG-CoA reductase inhibitor that is metabolized by the cytochrome P450 (CYP) 3A4. The calcium antagonist amlodipine is also metabolized by CYP3A4. The purpose of this study was to investigate drug interactions between amlodipine and simvastatin. Eight patients with hypercholesterolemia and hypertension were enrolled. They were given 4 weeks of oral simvastatin (5 mg/day), followed by 4 weeks of oral amlodipine (5 mg/day) co-administered with simvastatin (5 mg/day). Combined treatment with simvastatin and amlodipine increased the peak concentration (Cmax) of HMG-CoA reductase inhibitors from 9.6 ±3.7 ng/ml to 13.7±4.7 ng/ml (p<0.05) and the area under the concentration-time curve (AUC) from 34.3±16.5 ng h/ml to 43.9±16.6 ng h/ml (p<0.05) without affecting the cholesterol-lowering effect of simvastatin. This study is the first to determine prospectively the pharmacokinetic and pharmacodynamic interaction between amlodipine and simvastatin.

Altered pharmacokinetics and excessive hypotensive effect of candesartan in a patient with the CYP2C9*1/*3 genotype

An 89‐year‐old man with severe hypertension (190/82 mm Hg) and chronic heart failure (New York Heart Association class II) despite treatment with benidipine, doxazosin mesylate (INN, doxazosin), and furosemide was given oral candesartan cilexetil (4 mg/d), an angiotensin II type 1 receptor blocker metabolized via cytochrome P450 (CYP) 2C9. Two days later, he started to have severe dizziness and returned to the hospital on the fourth day without taking any of his medications. The blood pressure 30 hours after the last dose of candesartan was 126/64 mm Hg. Polymorphism analysis revealed the heterozygous poor metabolizer genotype CYP2C9*1/*3. The area under the concentration‐time curve and the mean residence time of candesartan were both increased 2.5‐fold, and the oral clearance of candesartan was 48% lower than that of the average elderly Japanese patient with hypertension. These results suggest that the CYP2C9*1/*3 genotype could be associated with decreased clearance and increased plasma concentration of candesartan, potentially enhancing its hypotensive effect.

Pharmacokinetics and pharmacodynamics of low doses of midazolam administered intravenously and orally to healthy volunteers

1. Midazolam, a short‐acting benzodiazepine, has been considered a probe for estimating hepatic and intestinal cytochrome P450 (CYP) 3A activity in humans. The aim of the present study was to evaluate the pharmacokinetics and pharmacodynamics of midazolam administered intravenously (i.v.) and orally (p.o.) at relatively low doses to healthy volunteers.

Sensitivity correction for the influence of the fat layer on muscle oxygenation and estimation of fat thickness by time-resolved spectroscopy

Abstract. Near-infrared spectroscopy (NIRS) has been used for noninvasive assessment of oxygenation in living tissue. For muscle measurements by NIRS, the measurement sensitivity to muscle (SM) is strongly influenced by fat thickness (FT). In this study, we investigated the influence of FT and developed a correction curve for SM with an optode distance (3 cm) sufficiently large to probe the muscle. First, we measured the hemoglobin concentration in the forearm (n=36) and thigh (n=6) during arterial occlusion using a time-resolved spectroscopy (TRS) system, and then FT was measured by ultrasound. The correction curve was derived from the ratio of partial mean optical path length of the muscle layer 〈LM〉 to observed mean optical path length 〈L〉. There was good correlation between FT and 〈L〉 at rest, and 〈L〉 could be used to estimate FT. The estimated FT was used to validate the correction curve by measuring the forearm blood flow (FBF) by strain-gauge plethysmography (SGP_FBF) and TRS (TRS_FBF) simultaneously during a reactive hyperemia test with 16 volunteers. The corrected TRS_FBF results were similar to the SGP_FBF results. This is a simple method for sensitivity correction that does not require use of ultrasound.

PI-23Influences of CYP2C9 genotype on pharmacokinetics and pharmacodynamics of benzbromarone

Benzbromarone is a widely used uricosuric drug which increases urinary excretion of uric acid and then lowers serum urate levels. Recently, it has been reported that benzbromarone is predominantly metabolized to 6‐hydroxybenzbromarone by CYP2C9, which is a polymorphic enzyme. The aim of this study was to clarify the influences of CYP2C9 genotype on pharmacokinetics and pharmacodynamics of benzbromarone.

Influences of CYP2C9 genotype and fluvastatin on pharmacokinetics and pharmacodynamics of nateglinide

The aim of this study was to clarify the influences of CYP2C9 genotype and co‐administration of fluvastatin on pharmacokinetics and pharmacodynamics of nateglinide.