Naoto Uemura

Human pharmacology of the methamphetamine stereoisomers.

To help predict the consequences of precursor regulation, we compared the pharmacokinetics and pharmacodynamics of the methamphetamine (INN, metamfetamine) stereoisomers.

Bioequivalence and Rapid Absorption of Zolmitriptan Nasal Spray Compared with Oral Tablets in Healthy Japanese Subjects

AbstractBackground and objective: Oral zolmitriptan is highly effective in the acute treatment of migraine. However, nausea and vomiting during attacks may limit the usefulness of oral medications. An alternative, nasal spray, formulation has been developed that demonstrates good efficacy, high tolerability and a very fast onset of action. This study assessed the pharmacokinetics and bioavailability of zolmitriptan and its active metabolite 183C91 in healthy Japanese subjects following single-dose (2.5 or 5mg) oral or intranasal administration. Methods: This was a single-centre, open-label, randomised, crossover study. Forty-eight subjects each received one oral and one intranasal dose of 2.5 or 5mg zolmitriptan, with a 72-hour washout period between doses. Blood was drawn at various timepoints from 2 minutes to 15 hours post-dose and urine was collected over the course of the study; samples were analysed for zolmitriptan and 183C91, from which pharmacokinetic parameters were calculated. Results: Zolmitriptan was detected in plasma 2 minutes after intranasal administration in the majority of subjects (∼75%) compared with 10 minutes after oral administration. The intranasal : tablet ratio for zolmitriptan area under the concentration-time curve from time zero to infinity was 0.924 (90% CI 0.826, 1.033) and 0.960 (90% CI 0.865, 1.066) for the 2.5 and 5mg doses, respectively. Other pharmacokinetic parameters were similar between the two formulations. While 183C91 appeared in the plasma concurrently to zolmitriptan after oral dosing, its appearance was delayed to approximately 30 minutes after intranasal dosing. Zolmitriptan was safe and well tolerated at both doses. Conclusions: The rapid absorption of zolmitriptan nasal spray may explain the faster relief from migraine reported in patients compared with oral zolmitriptan.

Simultaneous determination of grepafloxacin, ciprofloxacin, and theophylline in human plasma and urine by HPLC.

A specific and sensitive reversed-phase high-performance liquid chromatographic (HPLC) method has been developed and validated for the simultaneous determination of grepafloxacin, ciprofloxacin, and theophylline in human plasma and urine. This assay allows these drugs to elute and be resolved in a single chromatogram at 280 nm, using a linear gradient. The procedure involves liquid-liquid extraction. Separation was achieved on a C18 reversed-phase column. The quantification limits were 0.05 mg/L in plasma and 0.5 mg/L in urine for grepafloxacin and ciprofloxacin and 0.5 mg/L in plasma and urine for theophylline. Standard curves were linear (correlation coefficients >0.999) over the ranges 0.05 to 5 mg/L for grepafloxacin and ciprofloxacin in plasma, from 0.5 to 20 mg/L for theophylline in plasma, and from 0.5 to 500 mg/L for the three drugs in urine. The coefficients of variation for the three drugs were less than 10% for within- and between-day analyses. The recoveries averaged 94.5% for theophylline, 93% for ciprofloxacin, 93.7% for grepafloxacin, and 95.1% for the internal standard (IS). The assay can be used for pharmacokinetic studies of these drugs, to investigate the interaction of grepafloxacin and ciprofloxacin with theophylline, or for routine simultaneous monitoring of theophylline, grepafloxacin, and ciprofloxacin.

Determination of sparfloxacin in plasma and urine by a simple and rapid liquid chromatographic method

A simple, specific, sensitive, and rapid method has been developed and validated for the determination of sparfloxacin in human plasma and urine. The assay consisted of reversed-phase HPLC with ultraviolet detection. Plasma proteins were efficiently removed by precipitation with perchloric acid after the addition of grepafloxacin as an internal standard. For the urine samples, the only required sample preparation was dilution. Separation was achieved on a C18 reversed-phase column. The quantification limit was 0.025 mg/L in plasma and 0.5 mg/L in urine. The coefficients of variation (CV) were less than 10% for intra-day and inter-day analyses. The recovery of sparfloxacin added to plasma and urine ranged from 96.7% to 97.9%. The method has been successfully applied to pharmacokinetic studies.

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.

Clinical Drug–Drug Interaction Potential of BFE1224, Prodrug of Antifungal Ravuconazole, Using Two Types of Cocktails in Healthy Subjects

BFE1224, prodrug of ravuconazole, is a novel, once‐daily, oral, triazole antifungal drug, and currently in development for the treatment of onychomycosis. The clinical drug–drug interaction (DDI) potential of BFE1224 with cytochrome P450 (CYP) and transporter was assessed by using two types of cocktails in healthy subjects in separate clinical studies. The CYP and transporter cocktails consisted of caffeine/tolbutamide/omeprazole/dextromethorphan/midazolam used in study 1 and digoxin/rosuvastatin used in study 2. In addition, repaglinide was separately administered to the same subjects in study 2. There were no major effects on the pharmacokinetics of CYP and transporter substrates, except for an approximate threefold increase in midazolam exposure after oral administration of BFE1224. The clinical DDIs of BFE1224 were mild for CYP3A and minor for other major CYPs (CYP1A2/2C8/2C9/2C19/2D6) as well as those of P‐glycoprotein (P‐gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and OATP1B3.

Gly143Glu polymorphism of the human carboxylesterase1 gene in an Asian population.

Dear Editor, As Drs Zhu and Markowitz commented in their letter, it is widely recognized that carboxylesterase (CES) is an important enzyme that activates prodrugs in vivo. In our report, the interindividual variability observed in the metabolism of oseltamivir could not be explained on the basis of the CES1A1 genotypes and the number of CES1 functional genes [1]. However, the area under the curve (AUC) for oseltamivir for one subject in our study was approximately 10-fold higher than the corresponding AUCs for the rest of the subjects. A previous report has shown that two CES1 variants, Gly143Glu (rs71647871) and Asp260fs (rs7164782), reduce the hydrolytic activity of CES1 [2]. Moreover, the Gly143Glu variant has been shown to be associated with impaired oseltamivir metabolism [3, 4]. Although we are very interested in these polymorphisms, the Gly143Glu polymorphism appears to be extremely rare in the Asian population, as indicated by Zhu and Markowitz [2, 5], and the Asp260fs polymorphism is even rarer [2]. Gly143Glu is located in CES1A1 rather than CES1A2/CES1A3 [5], whereas Asp260fs is a mutation in the CES1A2 gene [5]. The transcriptional efficiency of CES1A1 is markedly higher than that of CES1A2. Therefore, the Gly143Glu mutation may be more important in CES1 metabolism. After submitting the manuscript, we examined the frequency of the Gly143Glu and Asp260fs polymorphisms in nearly 400 Japanese subjects. As expected, no such Glu variants were found in the DNA of the subjects, including those who participated in the reported study [1]. In addition, no Asp260fs variants were observed in our samples. Therefore, another hitherto unknown mutation in the CES1 gene may be involved in the slow oseltamivir metabolism in the poor metabolizer identified in our study. Additional studies are required to further elucidate the cause of the individual differences observed in CES1 substrate drug metabolism.

Effects of uric acid on vascular endothelial function from bedside to bench

This study was designed to investigate the effects of uric acid on vascular endothelial function in measurements carried out either at the bedside or the laboratory bench. First, we performed reactive hyperemia peripheral arterial tonometry using an EndoPAT 2000 device and measured serum uric acid levels in 92 outpatients with hypertension. The reactive hyperemia index (RHI) showed no correlation with serum uric acid level (R = −0.125, P = 0.235) in either overall patients or in a high-risk group of 51 patients with complications such as cardiovascular and cerebrovascular diseases, chronic kidney disease, and/or diabetes (R = −0.025, P = 0.860). However, in the remaining 41 patients in the low-risk group, RHI correlated negatively with serum uric acid level (R = −0.335, P = 0.032). Multiple regression analysis showed that serum uric acid level predicted RHI (R = −0.321, P = 0.043) in the low-risk group independent of age, body mass index, systolic blood pressure, and low density lipoprotein-cholesterol level. We then performed an in-vitro study using the WST-8 assay in human umbilical vein endothelial cells, which showed that hypoxic conditions reduced cell viability. Treatment with uric acid caused a further reduction in cell viability, while ascorbic acid improved viability. Using Western blot analysis, we observed that uric acid reduced endothelial nitric oxide synthase phosphorylation during hypoxic conditions. Serum uric acid level is associated with peripheral vascular endothelial function in patients with low-risk hypertension and uric acid could directly impair endothelial function under hypoxic conditions. These results are relevant to the interventional studies examining the cardiovascular protective effect of hypouricemic agents.

Application of Physiologically‐Based Pharmacokinetic Modeling to Predict Pharmacokinetics in Healthy Japanese Subjects

Pharmacokinetics (PKs) in Japanese healthy subjects were simulated for nine compounds using physiologically based PK (PBPK) models parameterized with physicochemical properties, preclinical absorption, distribution, metabolism, and excretion (ADME) data, and clinical PK data from non‐Japanese subjects. For each dosing regimen, 100 virtual trials were simulated and predicted/observed ratios for peak plasma concentration (Cmax) and area under the curve (AUC) were calculated. As qualification criteria, it was prespecified that >80% of simulated trials should demonstrate ratios to observed data ranging from 0.5–2.0. Across all compounds and dose regimens studied, 93% of simulated Cmax values in Japanese subjects fulfilled the criteria. Similarly, for AUC, 77% of single‐dosing regimens and 100% of multiple‐dosing regimens fulfilled the criteria. In summary, mechanistically incorporating the appropriate ADME properties into PBPK models, followed by qualification using non‐Japanese clinical data, can predict PKs in the Japanese population and lead to efficient trial design and conduct of Japanese phase I studies.