Hiromitsu Imai

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.

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.

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.

An Assessment of the Oral Bioavailability of Three Ca-Channel Blockers Using a Cassette-Microdose Study: A New Strategy for Streamlining Oral Drug Development

A cassette-microdose (MD) clinical study was performed to demonstrate its usefulness for identifying the most promising compound for oral use. Three Ca-channel blockers (nifedipine, nicardipine, and diltiazem) were chosen as model drugs. In the MD clinical study, a cassette-dose method was employed in which three model drugs were administered simultaneously. Both intravenous (i.v.) and oral (p.o.) administration studies were conducted to calculate the oral bioavailability (BA). For comparison, p.o. studies with therapeutic dose (ThD) levels were also performed. In all studies, blood concentrations of each drug were successfully determined using liquid chromatography-mass spectrometry with the lower limit of quantification of 0.2-2.0 pg/mL. Oral BA of nifedipine in the MD study was approximately 50% and in the same range with that obtained in the ThD study, whereas other two drugs showed significantly lower BA in the MD study, indicating a dose-dependent absorption. In addition, compared with the ThD study, absorption of nicardipine was delayed in the MD study. As a result, nifedipine was considered to be most promising for oral use. In conclusion, a cassette-MD clinical study is of advantage for oral drug development that enables to identify the candidate having desired properties for oral use.

Plasma capric acid concentrations in healthy subjects determined by high-performance liquid chromatography

Background Capric acid (FA10:0, decanoic acid) is a medium-chain fatty acid abundant in tropical oils such as coconut oil, whereas small amounts are present in milk of goat, cow, and human. Orally ingested FA10:0 is transported to the liver and quickly burnt within it. Only few reports are available for FA10:0 concentrations in human plasma. Methods Fasting (n = 5, male/female = 3/2, age 31 ± 9.3 years old) and non-fasting (n = 106, male/female = 44/62, age 21.9 ± 3.2 years old) blood samples were collected from apparently healthy Japanese volunteers. The total FA10:0 in the plasma were measured by high-performance liquid chromatography after derivatization with 2-nitrophenylhydrazine followed by UV detection. Results Inter and intra-assay coefficient of variation of FA10:0 assay at three different concentrations ranged in 1.7–3.9 and 1.3–5.4%, respectively, with an analytical recovery of 95.2–104.0%. FA10:0 concentration was below detection limit (0.1 µmol/L) in each fasting human plasma. FA10:0 was not detected in 50 (47.2%) of 106 non-fasting blood samples, while 29 (27.4%) plasma samples contained FA10:0 less than or equal to 0.5 µmol/L (0.4 ± 0.1), and 27 (25.5%) contained it at more than 0.5 µmol/L (0.9 ± 0.3). Conclusion A half of the non-fasting plasma samples contained detectable FA10:0. This simple, precise, and accurate high-performance liquid chromatography method might be useful for monitoring plasma FA10:0 during medium-chain triglycerides therapy.

The Pharmacokinetic Exposure to Fexofenadine is Volume‐Dependently Reduced in Healthy Subjects Following Oral Administration With Apple Juice

Pharmacokinetic exposures to fexofenadine (FEX) are reduced by apple juice (AJ); however, the relationship between the AJ volume and the degree of AJ‐FEX interaction has not been understood. In this crossover study, 10 healthy subjects received single doses of FEX 60 mg with different volumes (150, 300, and 600 mL) of AJ or water (control). To identify an AJ volume lacking clinically meaningful interaction, we tested a hypothesis that the 90% confidence interval (CI) for geometric mean ratio (GMR) of FEX AUCAJ/AUCwater is contained within a biocomparability bound of 0.5–2.0, with at least one tested volume of AJ. GMR (90% CI) of AUCAJ 150mL/AUCwater, AUCAJ 300mL/AUCwater, and AUCAJ 600mL/AUCwater were 0.903 (0.752–1.085), 0.593 (0.494–0.712), and 0.385 (0.321–0.462), respectively. While a moderate to large AJ‐FEX interaction is caused by a larger volumes of AJ (e.g., 300 to 600 mL), the effect of a small volume (e.g., 150 mL) appears to be not meaningful.

Pharmacokinetics of teriparatide after subcutaneous administration to volunteers with renal failure: a pilot study.

BACKGROUND AND OBJECTIVE Teriparatide acetate was developed in the form of a synthetic analogue of the Nterminal peptide (1-34) of human parathyroid hormone for the treatment of osteoporosis; it is administered subcutaneously once weekly. However, it is not known whether the pharmacokinetics (PK) of this drug is affected by renal impairment, and this study was conducted to look into this question. METHODS A multi-center study was conducted at six hospitals in Japan. Subjects were enrolled and grouped on the basis of renal function stratified as: normal function to mild renal impairment (estimated GFR(e-GFR): ≥ 60.0 mL/min/1.73 m2) (8 subjects), moderate impairment (eGFR: 30.0 - 59.9 mL/min/1.73 m2) (5 subjects), and severe impairment (eGFR: 15.0 - 29.9 mL/min/1.73 m2) (5 subjects). The PK parameters, blood and urine electrolytes concentrations, and safety profiles were assessed following a single subcutaneous injection of teriparatide acetate (56.5 μg as teriparatide). RESULTS The elimination half-life (t1/2) and the mean residence time extrapolated to infinity were significantly prolonged in the group with severe renal impairment (t1/2: 5.0 hours) compared with normal to mild and moderate impairment groups (t1/2: 1.5 hours and 1.2 hours, respectively). However, virtually all of the teriparatide was eliminated from the blood after 24 hours. Given that the drug is administered once weekly, it appeared highly unlikely that accumulation of the drug in the body would become a problem even with repeated administration. There were no particular problems with safety or tolerability. CONCLUSIONS In treatment with teriparatide acetate once-per week formulation, prescription at the usual dosage appears to be appropriate even in renally impaired patients.

Duration of drug interactions: putative time courses after mechanism-based inhibition or induction of CYPs.

In vivo metabolic capacity of cytochrome P450 (CYP) enzymes is affected by endogenous and exogenous factors. A large number of previous studies have revealed a large variety of substances produce clinically significant alterations in CYP enzymes. The resultant changes in systemic pharmacokinetics caused by inhibition or induction of CYPs in humans have been studied mostly using a cross-over design (e.g., drug plus placebo vs drug plus inhibitor) with a variety of washout periods. When we interpret drug–drug (food–drug) interaction studies, one of the important points to be considered is time-dependent recovery of altered enzyme activity after discontinuation of causative substances. The period has to be sufficient to avoid the carry-over effect of the proceeding treatment. Data concerning the time recovery of CYPs after inhibition or induction will provide essential information for designing studies of drug interactions with an adequate washout period. The recovery process after enzyme inhibition or induction is thought to be dependent mainly on the enzyme turnover, but it is difficult to evaluate this process directly in humans. To address this issue, an indirect method assessing timedependent changes in the pharmacokinetic parameters of enzyme-specific probe drugs after discontinuation of inhibitors or inducers has been adopted as an alternative. Although limited information is available so far, we provide an overview of previous studies conducted in humans regarding this theme.