Tsutomu Kotegawa

The effect of pregnancy on cytochrome P4501A2, xanthine oxidase, and N‐acetyltransferase activities in humans

Our objective was to evaluate the activity of cytochrome P4501A2 (CYP1A2), xanthine oxidase (XO), and N ‐acetyltransferase 2 (NAT2) from early to late pregnancy and after delivery.

Effect of St. John's wort on the pharmacokinetics of theophylline in healthy volunteers

The objective of this study was to investigate the effect of St. Johns wort (SJW, Hypericum perforatum) on the pharmacokinetics of theophylline in healthy volunteers. Twelve healthy Japanese male volunteers participated in this randomized, open‐labeled, crossover study. The subjects took an SJW caplet (300 mg) three times a day for 15 days. On day 14, they received a single oral dose of 400 mg of theophylline. They took the same dose of theophylline without SJW treatment on another occasion. Plasma and urine samples were obtained during a 48‐hour period after theophylline administration. Theophylline concentrations in plasma and urine, as well as the major metabolites (13U, 1U, 3X) in urine, were measured. SJW caused no significant changes in the pharmacokinetics of theophylline in plasma. SJW administration tended to increase the ratio of 1U/the total amount excreted in urine. However, no changes in the ratio of unchanged theophylline, 13U, and 3X were observed. It is unlikely that the effect of 15 days of treatment with SJW on CYPs is sufficient to cause a change in plasma theophylline concentrations.

Effect of the Treatment Period With Erythromycin on Cytochrome P450 3A Activity in Humans

The aim of the present study was to estimate the time course change in cytochrome P450 3A (CYP3A) activity during repeated doses of erythromycin. Twelve healthy male volunteers participated in this randomized, 4 × 4 Latin square design study. The pharmacokinetics of a single oral dose of midazolam, a probe for CYP3A activity, were assessed in 4 conditions: (1) midazolam (5 mg) without erythromycin (EM0), (2) erythromycin 2 days + midazolam (2.5 mg) (EM2), (3) erythromycin 4 days + midazolam (2.5 mg) (EM4), and (4) erythromycin 7 days + midazolam (2.5 mg) (EM7). The dose of erythromycin was 800 mg/d. Erythromycin produced a 2.3‐, 3.4‐, and 3.4‐fold increase in dose‐corrected area under the curve of midazolam for EM2, EM4, and EM7, respectively, as compared with EM0 (P <.05/6). A significant prolongation of terminal half‐life was observed in EM4 and EM7. The relationship between the duration of erythromycin treatment and total clearance of midazolam indicated that a plateau level of CYP3A inhibition can be achieved by 4 days or more of erythromycin treatment. The repeated treatment with erythromycin yields CYP3A inhibition in a duration‐dependent manner. A 4‐day course of erythromycin treatment produces 90% or more of the maximal inhibition of CYP3A in humans.

The recovery time‐course of CYP3A after induction by St John's wort administration

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT St Johns wort causes the induction of CYP3A. Little is known about how long the effect remains after cessation of St Johns wort. WHAT THIS STUDY ADDS The in vivo CYP3A activity returns progressively to the basal level approximately 1 week after cessation of St Johns wort administration AIMS To examine the recovery time course of CYP3A after enzyme induction by St Johns wort administration. METHODS The subjects were 12 healthy men, aged 20-33 years. On the first day, they received an oral dose of midazolam 5 mg without St Johns wort (day -14). From the next day, they took St Johns wort for 14 days. On the last day of St Johns wort treatment (day 0) and 3 and 7 days after completion of St Johns wort treatment (days 3 and 7), they received the same dose of midazolam. On each day, blood samples were obtained until 8 h after midazolam administration. Plasma concentrations of midazolam were measured by HPLC. Pharmacokinetic parameters of midazolam were determined using noncompartmental analysis. RESULTS Apparent oral clearance of midazolam was significantly increased after St Johns wort administration from 65.3 +/- 8.4 l h(-1) (day -14) to 86.8 +/- 17.3 l h(-1) (day 0). It returned to the control level 7 days after the completion of St Johns wort (day 7, 59.7 +/- 3.8 l h(-1)). No significant difference in the elimination half-life between the four periods of the study was observed. The changes in apparent oral clearance after St Johns wort discontinuation indicated that CYP3A activity recovers from enzyme induction with an estimated half-life of 46.2 h. CONCLUSIONS CYP3A activity induced by St Johns wort administration progressively returns to the basal level after approximately 1 week. This finding may provide useful information to avoid clinically significant interactions of St Johns wort with CYP3A substrates.

Apple juice greatly reduces systemic exposure to atenolol

AIM Fruit juice reduces the plasma concentrations of several β-adrenoceptor blockers, likely by inhibiting OATP2B1-mediated intestinal absorption. The aim of this study was to investigate the effects of apple juice on the pharmacokinetics of atenolol. METHODS Twelve healthy Korean volunteers with genotypes of SLCO2B1 c.1457C> T (*1/*1 (n = 6) and *3/*3 (n = 6)) were enrolled in this study. In a three-phase, one-sequence crossover study, the pharmacokinetics (PK) of atenolol was evaluated after administration of 50 mg atenolol. Subjects received atenolol with either 300 ml water, 1200 ml apple juice or 600 ml apple juice. RESULTS Apple juice markedly reduced the systemic exposure to atenolol. The geometric mean ratios (95% confidence intervals) of apple juice : water were 0.18 (0.13, 0.25, 1200 ml) and 0.42 (0.30, 0.59, 600 ml) for the AUC(0,t(last)). In this study, the PK parameters of atenolol responded in a dose-dependent manner to apple juice. CONCLUSIONS Apple juice markedly reduced systemic exposure to atenolol. The genetic variation of SLCO2B1 c.1457C>T had a minimal effect on the pharmacokinetics of atenolol when the drug was administered with water or apple juice.

Drug Interaction between Cimetidine and Timolol Ophthalmic Solution: Effect on Heart Rate and Intraocular Pressure in Healthy Japanese Volunteers

Systemic adverse effects of timolol ophthalmic solution given at usual therapeutic doses have been well characterized. Timolol is partially metabolized by cytochrome P450 (CYP) 2D6. Cimetidine inhibits the activity of cytochrome P450, including CYP2D6, leading to reduced systemic clearance of concomitant drugs. Coadministration of cimetidine has been speculated to affect the pharmacological effects of timolol ophthalmic solution, resulting in increased blood concentration. To evaluate whether administration of cimetidine with timolol ophthalmic solution increased the degree of beta‐blockade, 12 healthy Japanese male volunteers ages 19 to 26 received cimetidine (400 mg), an oral placebo, timolol maleate 0.5% (0.05 mL to each eye), or placebo eye drops in a randomized, double‐blind, Latin‐square design. The oral drug alone was given for 3 days, and on the 4th day, eye drops were applied after oral drug administration. At baseline and 1, 3, and 6 hours after eye drop administration, blood pressure and heart rate (HR) were measured before and after exercise. Intraocular pressure (IOP) was measured at rest. A visual analog scale (VAS) was used to assess subjective bodily feelings in exercise tolerance after every physical exercise. The exercise HR, exercise systolic blood pressure (SBP), and resting SBP were reduced following timolol with and without cimetidine compared with the placebo (p < 0.01, respectively). Administration of cimetidine with timolol ophthalmic solution resulted in additional reductions of the resting HR and IOP VAS detected a significant reduction in exercise tolerance from timolol ophthalmic solution (p < .05). In conclusion, administration of cimetidine with timolol ophthalmic solution increased the degree of beta‐blockade.

The Effect of Erythromycin and Clarithromycin on the Pharmacokinetics of Intravenous Digoxin in Healthy Volunteers

Several case reports have suggested an interaction between digoxin and macrolide antibiotics. The authors investigated the effect of erythromycin and clarithromycin on the pharmacokinetics of intravenously administered digoxin (0.5 mg) in healthy subjects. Nine male subjects participated in three studies (digoxin alone, digoxin with erythromycin, and digoxin with clarithromycin). Subjects took erythromycin (800 mg per day) or clarithromycin (400 mg per day) on the day before digoxin dosing and during the kinetic study. Neither of the macrolides affected serum digoxin concentration‐time curves. However, more than 1.3‐fold increases in urinary digoxin excretions were observed during erythromycin and clarithromycin coadministration compared with digoxin alone. There were significant differences in renal clearance between macrolide coadministration and the control condition (digoxin alone: 98.4 ml/min; digoxin with erythromycin: 137.3 ml/min; digoxin with clarithromycin: 133.6ml/min). In conclusion, neither erythromycin nor clarithromycin has a significant effect on serum digoxin disposition after an intravenous administration. Renal digoxin excretion is not inhibited but rather enhanced by both macrolides.

Pharmacokinetics and Pharmacodynamics of a New Transdermal Clonidine, M-5041T, in Healthy Subjects

The pharmacokinetic as well as the pharmacodynamic properties of a new transdermal clonidine, M‐5041T (M), and its safety were evaluated after single and repeated applications. In the single‐application study, one patch of M (4 mg → 6 mg → 8 mg) was applied for 3 days in eight healthy subjects. In the repeated‐application study, first (0–72 hours), second (72–144 hours), and third (144–216 hours) patches of M 6 mg were applied in seven healthy subjects. In the single‐application study, plasma clonidine concentration increased in a dose‐dependent manner after application of M. Maximum plasma concentration (Cmax) and area under the plasma concentration‐time curve (AUC) increased in a dose‐dependent manner, but the difference did not reach significance. Time to maximum concentration, elimination half‐life, and total and renal clearance did not differ significantly among three trials. Blood pressure (BP) decreased gradually after application of each dose of M. The BP‐lowering effect of M 8 mg was greater than that of M 4 mg and 6 mg. Adverse effects such as erythema and drowsiness were reported in some subjects. No subject had to be withdrawn from the study because of the appearance of adverse effects. In the repeated‐application study, plasma concentration of clonidine increased up to 48 hours after application of first patch, and thereafter remained within a relatively narrow range until removal of third patch. The Cmax and AUC did not differ significantly among three trials. Blood pressure during an active period decreased significantly during treatment with M, whereas BP at midnight did not change significantly. Two subjects complained of orthostatic vertigo caused by hypotension and were dropped out of the study. Mild erythema and systemic adverse effects were reported. These results suggest that M is a promising tool for the treatment of hypertension without unacceptable skin reactions. Orthostatic change in BP should be monitored carefully during treatment with M.

Effect of Fluconazole on the Pharmacokinetics and Pharmacodynamics of Oral and Rectal Bromazepam: An Application of Electroencephalography as the Pharmacodynamic Method

Quantitative analysis of electroencephalography (EEG) is used increasingly to evaluate the pharmacodynamics of benzodiazepines. The present study aimed to apply the EEG method as well as more traditional approaches to an interaction study of bromazepam and fluconazole. Twelve healthy male volunteers participated in a randomized, double‐blind, four‐way crossover study. The subjects received single oral or rectal doses of bromazepam (3 mg) after 4‐day pretreatment of oral fluconazole (100 mg daily) or its placebo. Plasma bromazepam concentrations were measured before and 0.5, 1,2,3,4, 6,12,22,46, and 70 hours after bromazepam administration. Pharmacodynamic effects of bromazepam were assessed using self‐rated drowsiness, continuous number addition test, and EEG. Fluconazole caused no significant changes in pharmacokinetics and pharmacodynamics of oral or rectal bromazepam. Rectal administration significantly increased AUC (1.7‐fold, p < 0.0001) and Cmax (1.6‐fold, p < 0.0001) of bromazepam. These changes following rectal dose may be due to avoidance of degradation occurringin the gastrointestinal tract. Rectal bromazepam also increased the area under the effect curves assessed by EEG (p < 0.05) and subjective drowsiness (p < 0.05). EEG effects were closely correlated with mean plasma bromazepam concentrations (r = 0.92, p < 0.001 for placebo; r = 0.89, p < 0.0001 for fluconazole). Thus, the EEG method provided pharmacodynamic data that clearly reflected the pharmacokinetics of bromazepam.

Determination of celiprolol in human plasma using high performance liquid chromatography with fluorescence detection for clinical application

A new method of analysis has been developed and validated for the determination of plasma celiprolol concentration. Plasma samples (1 ml) were pre-purified by solid-phase extraction with Bond Elut C18. The separation was achieved with XBridge C18 column (150 mm × 3.0mm i.d., 3.5 μm) at 35 °C using a mixture of acetonitrile and 10mM ammonium acetate buffer (pH 10.5) (34:66, v/v) under isocratic conditions at a flow rate of 0.4 ml/min. The peak was detected using a fluorescence detector at excitation 250 nm and emission 482 nm. Retention times for the internal standard (acebutolol) and celiprolol were 4.2 min and 6.3 min, respectively. Calibration curves were linear over the range of 1.0-1000 ng/ml (r>0.999), with a limit of quantification at 1.0 ng/ml. Intra- and inter-assay precision (relative standard deviation) were less than 13.3% and the accuracy (relative error) was -5.1% to 11.5% at four different concentrations. This proposed method was successfully applied to a study of pharmacokinetic interactions between celiprolol and apple juice in humans.