Effects of rifampicin on the pharmacokinetics and safety of carotegrast methyl in healthy subjects: A randomized 2 × 2 crossover study.

AIMS: To evaluate the effect of the combination of carotegrast methyl with rifampicin, a potent inhibitor of organic anion transporter polypeptide, on the pharmacokinetics (PKs), safety and tolerability of carotegrast methyl. METHODS: In this 2 × 2 crossover study in 20 healthy Japanese adults, 10 subjects received carotegrast methyl 960 mg and rifampicin 600 mg on day 1 and received carotegrast methyl 960 mg on day 8. The subjects in the other sequence received the same treatments but in the opposite order. The 90% confidence interval (CI) of the geometric mean ratio of the Cmax and AUC0-t for carotegrast, the main active metabolite of carotegrast methyl, with/without rifampicin was calculated. If the 90% CI fell within the range of 0.80-1.25, this indicated the absence of any drug-drug interaction. Adverse events (AEs) were monitored. RESULTS: The geometric mean ratios (90% CI) of the Cmax and AUC0-t for carotegrast with/without rifampicin were 4.78 (3.64-6.29) and 5.59 (4.60-6.79), respectively, indicating that carotegrast has a PK interaction with rifampicin. The combination with rifampicin increased the exposure of carotegrast and also that of its metabolites. The incidence of any AEs with/without rifampicin was five (25.0%) and one (5.0%), respectively. CONCLUSIONS: Coadministration of carotegrast methyl with rifampicin significantly increased the exposure of carotegrast compared with carotegrast methyl administration alone. In this single dose study, the incidence of AEs of carotegrast methyl with rifampicin increased compared with carotegrast methyl alone, but the incidence of adverse drug reactions did not increase with combination administration.

Evaluation of the potential drug-drug interactions of carotegrast methyl with midazolam, prednisolone or atorvastatin in healthy adults.

AIMS: This study evaluated drug-drug interactions between the CYP3A4 inhibitor carotegrast methyl and the other CYP3A4 substrates, midazolam, atorvastatin and prednisolone. METHODS: A total of 88 healthy volunteers orally received carotegrast methyl 960 mg 3 times daily for 14 days. A single oral (5 mg) or intravenous (0.017 mg kg-1 ) midazolam, oral (5 mg) prednisolone or oral (10 mg) atorvastatin was administered before, with and after carotegrast methyl treatment. When the 90% confidence interval (CI) for the geometric mean ratios of the pharmacokinetic (PK) parameters with coadministration with carotegrast methyl (Day 14) to those before carotegrast methyl administration was between 0.80 and 1.25, no PK interaction were deemed. RESULTS: The Cmax and AUC0-t of oral midazolam before administration of carotegrast methyl were 30.9 ± 9.8 ng mL-1 and 74.5 ± 21.9 ng h mL-1 , respectively. The geometric mean ratio of the Cmax and AUC0-t of midazolam on Day 14 to those on Day -1 was 1.86 (90% CI, 1.64-2.11) and 3.07 (90% CI, 2.81-3.35), which did not fall within the range of 0.80-1.25, suggesting that carotegrast methyl had a PK interaction with midazolam. Similar PK interactions were found for intravenous midazolam and atorvastatin, but not for prednisolone. The inhibitory effect of carotegrast methyl on CYP3A4-mediated metabolism of midazolam and atorvastatin had almost disappeared by 14 days after the end of administration. CONCLUSION: Carotegrast methyl was classified as a moderate CYP3A4 inhibitor in humans. Carotegrast methyl might enhance the action of drugs that are metabolized by CYP3A4.

Association between psychomotor function and ALDH2 genotype after consuming barley shochu: A randomized crossover trial.

Sustained exposure to acetaldehyde, the major metabolite of ethanol, may influence psychomotor performance even after the breath ethanol level significantly drops several hours following ethanol consumption. We examined the relationship between psychomotor function and changes in exhaled ethanol and acetaldehyde concentrations after consuming a low dose (0.33 g/kg) of barley shochu, a traditional Japanese distilled alcohol beverage, at the point when the exhaled ethanol concentrations dropped below 78,000 parts per billion (0.15 mg/L), the standard threshold for driving under the influence of alcohol in Japan. We assessed how the genetic polymorphisms of rs671 G/G homozygous (*1/*1) and G/A heterozygous (*1/*2) of ALDH2 influenced the kinetics of ethanol and acetaldehyde in exhaled air and psychomotor dynamics using the Digit Symbol Substitution Test (DSST), Critical Flicker Fusion Test (CFFT), and visual analogue scale (VAS) up to 12 h after shochu or water intake. There was no significant difference in DSST and CFFT scores depending on genotype; however, the time required for the DSST to attain the level prior to drinking was longer in the ALDH2 *1/*2 group than in the *1/*1 group. In the VAS test, facial flushing and mood elevation tended to be higher in the *1/*2 group after shochu consumption. VAS scores for mood elevation and facial flushing correlated with acetaldehyde concentration in exhaled breath. These results indicate that DSST recovery tends to be slower and mood elevation higher in the ALDH2 *1/*2 group even when exposed to a low dose of alcohol.

Pharmacokinetics of lanoconazole in human skin after repeated topical application.

Drug disposition after topical application to the skin has not been fully elucidated, especially after repeated application. We conducted a clinical trial to evaluate the pharmacokinetics in the stratum corneum of healthy adults after repeated application of lanoconazole cream as a model drug. We applied 25 mg of 1% lanoconazole cream onto the pre-specified areas on the participants' back once daily for 5 days. The stratum corneum was sampled twice on each study day using a standardized tape-stripping method, and the amount of lanoconazole contained in the samples was quantified using the tandem mass spectrometry method. The obtained data were used to evaluate lanoconazole pharmacokinetics in the stratum corneum. The amount of lanoconazole in the stratum corneum after once daily repeated administration reached a steady state on day 3, and it was eliminated from the stratum corneum with a half-life of approximately 11 h after discontinuing application.

A phase I study to evaluate safety, pharmacokinetics, and pharmacodynamics of respiratory syncytial virus neutralizing monoclonal antibody MK-1654 in healthy Japanese adults.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among all infants worldwide and remains a significant cause of morbidity and mortality. To address this unmet medical need, MK-1654, a half-life extended RSV neutralizing monoclonal antibody, is in clinical development for the prevention of RSV disease in infants. This was a phase I, randomized, placebo-controlled, single-site, double-blind trial of MK-1654 in 44 healthy Japanese adults. The safety, tolerability, pharmacokinetics, antidrug antibodies (ADAs), and serum neutralizing antibody (SNA) titers against RSV were evaluated for 1 year after a single intramuscular (i.m.) or intravenous (i.v.) dose of MK-1654 or placebo in five groups (100 mg i.m., 300 mg i.m., 300 mg i.v., 1000 mg i.v., or placebo). MK-1654 was generally well-tolerated in Japanese adults. There were no serious drug-related adverse events (AEs) reported in any MK-1654 recipient and no discontinuations due to any AEs in the study. The half-life of MK-1654 ranged from 76 to 91 days across dosing groups. Estimated bioavailability was 86% for 100 mg i.m. and 77% for 300 mg i.m. One participant out of 33 (3.0%) developed detectable ADA with no apparent associated AEs. The RSV SNA titers increased in a dose-dependent manner among participants who received MK-1654. These data support the development of MK-1654 for use in Japanese infants.

The µ-opioid receptor gene polymorphism 118A>G weakens the pharmacological action of buprenorphine.

AIMS: Opioids are commonly used analgesics for moderate to severe pain, but levels of drug effect vary among individuals. As for the mechanisms underlying these individual differences, there have been reports suggesting effects of polymorphisms in the gene encoding µ-opioid receptor (OPRM1). However, whether these polymorphisms affect the actions of µ-opioid receptor partial agonists has yet to be determined. This study aimed to assess differences in the pharmacological actions of buprenorphine, a µ-opioid receptor partial agonist, due to a polymorphism (A118G, rs1799971) in the OPRM1 gene in humans. MATERIALS AND METHODS: Ten healthy adult men (5 with OPRM1 c.118AA and 5 with OPRM1 c.118GG) received a single intravenous dose of buprenorphine hydrochloride at 0.001 mg/kg. Blood samples were collected up to 360 minutes after drug administration to assess the pharmacokinetics of buprenorphine. Nociceptive thresholds (temperature), digital symbol substitution test (DSST), and visual analog self-rating scale (VAS) for subjective symptoms were also evaluated over time to assess the pharmacodynamics. RESULTS: Nociceptive thresholds were significantly increased in the AA as compared to the GG group after buprenorphine administration (p = 0.025), while the DSST scores were significantly lower in the AA group (p < 0.001). The VAS scores for drowsiness (p < 0.001), malaise (p < 0.001), nausea (p < 0.001), and euphoria (p = 0.004) were higher in the AA than in the GG group. CONCLUSION: Levels of pharmacological actions of a µ-opioid receptor partial agonist vary in accordance with a polymorphism in the OPRM1 gene (A118G).

Optical frequency distribution using laser repeater stations with planar lightwave circuits.

We report a cascaded optical fiber link which connects laboratories in RIKEN, the University of Tokyo, and NTT within a 100-km region using a transfer light at 1397 nm, a subharmonic of the Sr clock frequency. The multiple cascaded link employing several laser repeater stations benefits from a wide feedback bandwidth for fiber noise compensation, which allows constructing optical lattice clock networks based on the master-slave configuration. We developed the laser repeater stations based on planar lightwave circuits to significantly reduce the interferometer noise for improved link stability. We implemented a 240-km-long cascaded link in a UTokyo-NTT-UTokyo loop using light sent from RIKEN via a 30-km-long link. In environments with large fiber noise, the link instability is 3 × 10-16 at an averaging time of 1 s and reaches 1 × 10-18 at 2,600 s.

Development of a simultaneous quantitation for short-, medium-, long-, and very long-chain fatty acids in human plasma by 2-nitrophenylhydrazine-derivatization and liquid chromatography-tandem mass spectrometry.

Fatty acids (FA) have been important in clinical diagnosis for long, which makes the increasing need for a fast, reliable, and economic approach to determine FA of short-, medium-, long-, and very long-chain by widely available equipment and with high-throughput capacity. In the present work, 2­nitrophenylhydrazine derivatization coupling with LC-MS/MS detection was utilized to simultaneously quantitate 18 FAs ranging from C4 to C26 in human plasma. The sample preparation protocol was optimized and extracting with diethyl ether­potassium phosphate buffer twice was found as the highest efficiency along with economic feasibility. Under the optimized conditions, all the FA showed excellent linearity (R2 > 0.999 for each), sufficient sensitivity (LOD 0.2-330 fmol and LOQ 2.3-660 fmol for all), favorable accuracy (recovery ranged from 98.1 ±â€¯3.6% to 104.9 ±â€¯5.5% with coefficient of variation no >8.6% for all), and negligible matrix effect. In the clinical application on 30 healthy subjects, compared with the previous HPLC-UV method, the developed method showed high reliability, as well as reduced time and reagent costs. The established method showed the potential to apply to not only diagnostic practice, but also nutritional and epidemiological studies.

No Effect of Digoxin on Rosuvastatin Pharmacokinetics in Healthy Subjects: Utility of Oita Combination for Clinical Drug-Drug Interaction Study.

This study evaluated the utility of combination of digoxin (0.25 mg) and rosuvastatin (5 mg) as a new transporter (P-glycoprotein/breast cancer resistance protein/organic anion-transporting polypeptide (OATP)1B1/OATP1B3) probe cocktail (Oita combination) for drug-drug interaction (DDI) studies by demonstrating lack of DDI of digoxin on the pharmacokinetics (PKs) of rosuvastatin, as it was already known that rosuvastatin did not affect digoxin PK. This was an open-label, two-period study in which the primary end points were the geometric mean ratio (GMR) of the area under the plasma rosuvastatin concentration-time curve from time zero to last (AUClast ) after rosuvastatin administration combined with digoxin to that after rosuvastatin administration alone and its 90% confidence interval (CI). As the GMR of AUClast was 0.974 and its 90% CI was 0.911-1.042, it was judged that digoxin does not affect rosuvastatin PK. Results of this study have rationalized utility of the Oita combination as a transporter probe cocktail for clinical DDI studies.

Histological evaluation of nintedanib in non-alcoholic steatohepatitis mice.

AIMS: In addition to potentially progressing to either cirrhosis or hepatocellular carcinoma, non-alcoholic steatohepatitis (NASH) is currently the leading indication for liver transplantation. Nintedanib has been clinically used to treat idiopathic pulmonary fibrosis for many years, but its effects in an animal model of NASH have not been tested. The purpose of this study was to evaluate the effects of nintendanib on NASH in choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD)-fed mice. MAIN METHODS: Male C57BL/6 mice were fed a CDAHFD for 6 weeks to induce NASH with liver fibrosis, and they were administered nintedanib (60 mg/kg/day) or distilled water orally in the last 2 weeks of the feeding period. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), triglyceride, and non-esterified fatty acids concentrations were measured. Serum cytokeratin 18 fragment (CK18) was detected using ELISA. Liver tissue sections from mice were stained with hematoxylin-eosin and Masson's trichrome to assess the level of steatohepatitis and fibrosis. KEY FINDINGS: CDAHFD-fed mice exhibited higher serum ALT, AST, and ALP levels compared with Control mice. A significant increase in the serum CK18 level was observed in the NASH group compared with the Control group. CDAHFD feeding also enhanced steatohepatitis and hepatic fibrosis pathological features, which were reduced after nintedanib treatment. SIGNIFICANCE: Nintedanib exerted anti-inflammatory and anti-fibrotic effects in CDAHFD-induced NASH mice.

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.

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

A simple and reliable method for the determination of domperidone in human plasma has been developed. Plasma samples (1mL) were pre-purified by a solid-phase extraction with Bond Elut(®) C18. The separation was achieved with XBridge™ C18 column (150mm×4.6mm i.d., 5µm) at 40°C. The mobile phase was a mixture of acetonitrile and 10mM ammonium acetate buffer (36:64, v/v), adjusted to pH 9.4 with 20% ammonium solution at a flow rate of 1.0mL/min. The peak was detected using fluorescence detector at excitation 282nm and emission 328nm. Retention times for domperidone and internal standard (propranolol) were 8.3min and 11.2min, respectively. The method showed a good linearity (r>0.999), precision (relative standard deviations <10.6%), and extraction recovery (85.7-99.7%) over a concentration of 1-100ng/mL. The lower limit of quantification (LLOQ) was 1.0ng/mL. This proposed method was successfully applied to a pharmacokinetic interaction study of domperidone in healthy Japanese volunteers.

The effect of experimentally induced sleep disturbance on the pharmacokinetics of lorazepam in healthy volunteers.

The aim of this study was to evaluate the effect of sleep disturbance on the pharmacokinetics, especially on the absorption, of lorazepam in humans. Eight healthy male volunteers received a single oral dose of lorazepam 1 mg before sleep on two occasions in a cross-over design. In either of the two doses, subjects were intermittently exposed to noise for 1.5 hours after oral lorazepam administration. Plasma lorazepam concentrations were measured by HPLC. The exposure to noise significantly prolonged tmax (control vs. noise: 2.0 vs. 3.0 hours) and significantly decreased AUC of lorazepam in the absorption phase. The reduction was 54% (95% CI, 15 - 75%) and 24% (3 - 40%) for AUC (0 - 1 hours) and AUC (0 - 3 hours), respectively. No significant changes were observed in other pharmacokinetic parameters. The results of this study suggest that the onset of drug action after oral lorazepam administration can be altered by sleep disturbance.

[Determination of triazolam and midazolam in human plasma using gas chromatography with microelectron capture detection for clinical application].

A method for the simple and reliable determination of triazolam and midazolam in human plasma using gas chromatography with microelectron capture detection has been developed. Samples (0.5 mL of plasma) were prepared using a simple solvent extraction with 3% isoamyl alcohol/benzene in the presence of NaOH. Two microlitres of the extract were injected onto the capillary column ((5%-phenyl)-methylpolysiloxane). The method was found to be valid in terms of selectivity, linearity, precision, accuracy, and recovery over the concentration range of 0.2 to 20 ng/mL for triazolam, and from 0.5 to 200 ng/mL for midazolam, respectively. Intra- and inter-day precisions determined at three concentrations were from 4.1 to 9.3% for triazolam and from 2.9 to 13.0% for midazolam. The accuracies were within 17.7% for triazolam and within 13.0% for midazolam. This proposed method was successfully applied to a pharmacokinetic study of triazolam or midazolam in healthy volunteers.

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.

The effect of carboxylesterase 1 (CES1) polymorphisms on the pharmacokinetics of oseltamivir in humans.

PURPOSE: The aim of this study was to examine whether carboxylesterase 1 (CES1A) genetic polymorphisms affect the pharmacokinetics of oseltamivir. METHODS: Thirty healthy Japanese male and female subjects ranging in age from 20 to 36 years voluntarily participated in this study. These subjects were administered a single 75-mg dose of oseltamivir (Tamiflu®), and blood samples were collected predose and up to 24 h after oseltamivir administration. Oseltamivir and its active metabolite, oseltamivir carboxylate, were measured by liquid chromatography-time of flight/mass spectrometry with solid-phase extraction. The CES1A diplotypes [a combination of haplotypes A (CES1A3-CES1A1), B (CES1A2-CES1A1), C (CES1A3-CES1A1variant), and D (CES1A2-CES1A1variant)] were determined by PCR-restriction fragment length polymorphism analysis and direct sequencing. RESULTS: All subjects completed the study according to the protocol, and no clinically meaningful adverse events were attributable to the administration of oseltamivir. No significant differences in the pharmacokinetic parameters of oseltamivir and oseltamivir carboxylate were observed according to CES1A genotype. In one subject, the peak concentration and area under the concentration-time curve (AUC) of oseltamivir were approximately tenfold higher than the mean values of the other subjects. CONCLUSIONS: In our study, the known interindividual variability in oseltamivir metabolism was not explained by CES1A genetic polymorphisms, but are likely the result of other factors. While one subject was found to exhibit an approximate tenfold higher AUC than the other subjects, no abnormal behaviors were associated with the increased oseltamivir plasma concentrations. Further studies are required to reveal the cause of individual differences in CES1A metabolism and the abnormal behavioral effects of oseltamivir.

Effect of renal impairment on the pharmacokinetics of memantine.

The effect of renal impairment on the pharmacokinetics of a single oral dose of memantine (10 mg) was determined in Japanese subjects. Subjects were assigned to four groups based on baseline creatinine clearance (CL(CR)): normal renal function (> 80 mL/min, n = 6), and mild (50 to ≤ 80 mL/min, n = 6), moderate (30 to < 50 mL/min, n = 6), and severe renal impairment (5 to < 30 mL/min, n = 7). Mean memantine maximum plasma concentration (C(max)) was similar in the groups (12.66, 17.25, 15.75, and 15.83 ng/mL, respectively), as was mean time to C(max) (6.2, 5.2, 4.3, and 5.4 h, respectively). However, exposure to memantine determined from mean area under the plasma concentration-time curve was 1.62-, 1.97-, and 2.33-times higher in subjects with mild, moderate, and severe renal impairment, respectively, as compared to controls with normal renal function. Mean memantine plasma elimination half-life increased according to increasing renal impairment (61.15, 83.00, 100.13, and 124.31 h, respectively), while mean cumulative urinary recovery of unchanged memantine in 72 h after dosing decreased according to increasing renal impairment (33.68%, 33.47%, 23.60%, and 16.17%, respectively). These results are the same as those in the previous study on caucasian individuals, when compared per body weight. It is suggested that the dose of memantine should be halved in patients with renal impairment.

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.

Itraconazole and domperidone: a placebo-controlled drug interaction study.

PURPOSE: To determine the influence of itraconazole on the pharmacokinetics, and the CNS and prolactin-elevating effects of domperidone in humans. METHODS: Fifteen healthy volunteers received either itraconazole (200 mg daily) or placebo for 5 days with a double blind, randomized, cross-over design. A single oral 20-mg dose of domperidone was administered to subjects on day 5. Plasma domperidone and serum prolactin concentrations were measured. The effects of domperidone on CNS were also assessed using self-rating scales and electroencephalography. RESULTS: Itraconazole significantly increased domperidone AUC(0-∞) (3.2-fold) and C(max) (2.7-fold) compared with placebo, but had no significant effect on the elimination half-life of domperidone. The CNS effects of domperidone assessed by self-rating of mood and electroencephalography, and the prolactin-elevating effect, were not significantly affected by itraconazole. A counterclockwise hysteresis was evident in the relationship between plasma domperidone and serum prolactin concentrations. Itraconazole shifted the hysteresis to the right. Concentration-effect modeling procedures yielded a significant linear relationship between hypothetical effect site domperidone concentrations and prolactin levels. Itraconazole reduced the slope of the linear relationship. CONCLUSIONS: Itraconazole significantly increased plasma domperidone concentrations. The interaction is probably mainly due to a reduced first pass elimination by inhibition of CYP3A and/or MDR1. The clinical significance of the altered relationship between domperidone concentrations and prolactin levels caused by itraconazole is still to be determined.