Eiji Owada

Hokkaido Pharmaceutical University School of Pharmacy, Otaru, Hokkaidō, Japan

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Publications (34)46.02 Total impact

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    ABSTRACT: UDP-glucuronocyltransferase 2B7 (UGT2B7) catalyzes glucuronidation of various types of endogenous compounds and drugs, but the genetic basis of interindividual variation in the metabolism of these substances has not yet been sufficiently elucidated. In addition, information about single nucleotide polymorphisms (SNPs) and haplotypes of the UGT2B7 gene that encode the enzyme in the Japanese population is still far from sufficient. We paid special attention to and performed an investigation on -327A > G, -161T > C, -138G > A, and -125T > C in the proximal promoter region, which is regarded as being important for the transcription of the UGT2B7 gene, and also on 211G > A and 802C > T, i.e., non-synonymous SNPs of exon 1 and exon 2 that encode the substrate binding domain. Their genotypes were determined by PCR-direct sequencing. As a result of genotyping, the minor allele frequencies in 160 Japanese individuals were found to be as follows: -327SNP A allele, 0.244; -161SNP T allele, 0.244; -138SNP A allele, 0; -125SNP C allele, 0.078; 211SNP T allele, 0.148 and 802SNP T allele, 0.244. By computational haplotype analysis, it was found that these regions formed a linkage disequilibrium block, and the presence of five haplotypes was demonstrated. These results suggest that the haplotype structure in the Japanese population is different from that of other ethnic groups.
    No preview · Article · Apr 2006 · Clinical Biochemistry
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    ABSTRACT: To determine a pharmacodynamic model for warfarin under thrombo-test (TT) monitoring, we examined the correlation between steady state TT values, warfarin dosage and serum concentration in patients receiving warfarin treatment. Based on the results, we developed a pharmacodynamic model relating TT values to free warfarin concentrations.We studied 19 cardiac patients receiving warfarin anticoagulant therapy in whom warfarin serum concentrations and TT values were considered to be in a steady state. While no correlation was observed between steady-state TT values and either warfarin dosage per kilogram body weight or total warfarin concentration, a significant negative correlation was observed between steady-state TT values and free warfarin concentrations (r=-0.561, p<0.05). We then developed a pharmacodynamic model expressing the relationship between steady-state TT values and free warfarin concentrations using nonlinear least-squares fitting. The AIC (Akaike's Information Criterion) of the sigmoid Emax model was 171.2, a value less than the AICs of the linear, log-linear and Emax models.In conclusion, a sigmoid Emax model expressing the relationship between TT values and free warfarin concentration is an appropriate pharmacodynamic model for warfarin when TT values are used as an indicator of coagulability.
    No preview · Article · Jan 2006
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    ABSTRACT: To establish guidelines for avoiding the side effects of mycophenolate mofetil (MMF) in renal transplant recipients with tacrolimus (TAC)-based immunosuppression, the relationship between the daily dose of MMF and the occurrence of side effects was analyzed in this study. The frequency of side effects was investigated retrospectively in 28 renal transplant recipients treated with immunosuppression (men 14 : women 14, age: 33.0+/-12.4 years, weight: 50.9+/-10.7 kg). Cytomegalovirus (CMV) infection and diarrhea were the most frequent side effects in the early transplant phase (from transplantation to 3-month biopsy) in the recipients. In 18 recipients, excluding the recipients with risk factors for CMV infection (ABO-incompatible transplantation, donor (+)/recipient (-) CMV serostatus, etc.), no significant correlation was shown between the daily dose of MMF and the occurrence of CMV infection in the two-sample t-test. On the other hand, the daily dose in the diarrhea group (33.2+/-4.3 mg/kg/day, n = 5) was significantly higher than that in the no-diarrhea group at 30 days (28.4+/-3.7 mg/kg/day, n = 23, p < 0.05) and 90 days (25.7+/-4.4 mg/kg/day, n = 21, p < 0.005) after transplantation, respectively. The receiver-operating characteristic (ROC) curve also revealed that the risk of diarrhea increased with a daily MMF dose higher than 30 mg/kg/day. In conclusion, to decrease the risk of diarrhea in the early transplant phase in renal transplant recipients with TAC-based immunosuppression, the daily dose of MMF should not be more than 30 mg/kg/day.
    No preview · Article · Mar 2005 · Yakugaku zasshi journal of the Pharmaceutical Society of Japan

  • No preview · Article · Jan 2004
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    ABSTRACT: P-glycoprotein (P-gp) is significant from the viewpoint of pharmacokinetics/pharmacodynamics (PK/PD). MDR1 gene encodes P-gp and has a wide variety of SNPs. As the SNPs may be one of the factors that induce pharmacogenetic individual difference, haplotype analysis is necessary to evaluate the PK/PD. The SNPs of the detected MDR1 were -129T>C, 325G>A, 2677G>T/A, and 3435C>T. For the analysis of linkage disequilibrium (LD) and haplotype analysis, and for the reconstruction of the haplotype pair, ARLEQUIN and PHASE were employed. The result of the chi(2) test detected significant LD between -129 and 2677, -129 and 3435, and 2677 and 3435. There were 9 haplotypes: T-G-C, T-T-C, C-T-C, T-A-C, C-A-C, T-G-T, T-T-T, C-G-T, and C-T-T. LD was found among the positions -129, 2677 and 3435. As a result, 9 haplotypes exists in the Japanese population. These results suggest that it would be necessary to give consideration to haplotype for the purpose of evaluating the PK/PD of the drugs transported by P-gp.
    No preview · Article · Oct 2003 · Clinical Biochemistry

  • No preview · Article · Jan 2001
  • Nahoko Kurosawa · Eiji Owada · Keiji Ito
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    ABSTRACT: To assess avoidance of hepatic first-pass effect of drugs, we undertook in situ experiments using rectal administration of lidocaine in the rabbit. We also employed in situ duodenal route to estimate first-pass metabolism across the gastrointestinal mucosa. Rabbits were administered lidocaine HCl intravenously (i.v., 50 mg/20 min) and portally (i.p.v., 33.3, 16.7, 8.3 mg/20 min) and avoidance of hepatic first-pass effect (Fh) was calculated from the area under curve (AUC). Fh was about 30% and did not vary with increasing i.p.v. dose. Intravenous and i.p.v. administration was followed by duodenal (i.d.) or rectal (i.r.) administration and the absorption (fa), Fh, and avoidance of first-pass effect in the duodenal mucosal membrane (Fm) were determined. With i.d. administration, lidocaine was absorbed completely with negligible first-pass effect in the mucosa (Fm=1). On the other hand, while lidocaine was also absorbed almost completely via the i.r. route, avoidance of first-pass effect was 60%, representing twice the bioavailability via i.d. administration. On the basis of these data, assuming that the first-pass effect in the rectal mucosa was negligible, we estimate the fraction of rectal venous drainage bypassing the portal circulation and thus hepatic metabolism (fnh) to be about 40%.
    No preview · Article · Jan 1999 · Biopharmaceutics & Drug Disposition
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    ABSTRACT: Urinary excretion of mefenamic acid (MA) and its two oxidative metabolites, M-I (3'-hydroxymethyl derivative) and M-II (3'-carboxyl derivative), and their glucuronides was investigated in preterm infants undergoing MA therapy. MA was given orally at a dose of 2 mg/kg and the dose was repeated every 24 h a maximum of three times. Urine was collected for up to 5 d after the last dose, and MA and the metabolites were determined by a newly developed HPLC. The cumulative amounts of MA and the metabolites excreted in the urine varied from 7 to 46% of the total dose administered, and were less than those reported in adults and children. Significant correlation was observed between the plasma half-life of MA and the cumulative amount of MA and the metabolites excreted in the urine. These results suggest that long plasma half-lives of MA observed in preterm infants are due mainly to low activity of drug metabolizing enzyme(s). In an infant who received the two regimens of MA therapy about 2 weeks apart, the plasma half-life of MA was shortened and the urinary excretion of the MA metabolites including their glucuronides was greatly increased during this period. It is suggested that the activities of both cytochrome P-450(s) and glucuronyltransferase(s) related to MA metabolism rapidly increased during the first month of the infant's life.
    No preview · Article · May 1997 · Biological & Pharmaceutical Bulletin
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    ABSTRACT: The pharmacokinetics of mefenamic acid (MA), 2 mg/kg, were studied in 17 preterm infants with symptomatic patent ductus arteriosus. They were given this dosage orally at 24 h intervals. There were marked inter-individual differences in some of the pharmacokinetic parameters after the first dose; peak plasma concentration (Cmax) varied from 1.2 to 6.1 micrograms/mL with a mean of 3.8 micrograms/mL, time to reach Cmax (tmax) varied from 2 to 18 h with a mean of 7.7 h and plasma half-life (t1/2) varied from 3.8 to 43.6 h with a mean of 18.7 h. The group of infants (10/17) who had ductus closure after the first dose had significantly lower clearance (P < 0.01), longer t1/2 (P < 0.01) and higher 24 h plasma concentration (P < 0.001) compared to the group of infants (7/17) who had no ductus closure after the first dose. It appeared that the plasma concentration of MA had to be above 2.0 micrograms/mL and maintained at this concentration for at least 12 h for MA associated with ductus closure in preterm infants to take effect. In view of the inter-individual variation of plasma MA concentration and the effective plasma concentration, we suggest that measurement of the plasma concentration should be done 24 h after the first dose. This might be useful for safe and effective therapy for infants with ductus closure failure after the first dose.
    No preview · Article · Aug 1994 · Acta paediatrica Japonica; Overseas edition
  • N Kurosawa · E Owada · K Ito
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    ABSTRACT: To understand the previous result of higher bioavailability of rectal salbutamol (SB) compared with oral SB, in situ experiments using rabbit duodenal and rectal loop were carried out. After the intravenous (i.v.) and intraportal (i.p.) dosing of SB, fraction of dose which avoids the hepatic first-pass-effect (Fh) was calculated from the areas under the blood concentration-time curve (AUC). The Fh was about 10% and unchanged significantly with increasing i.p. dose (5-20 mg). Intraduodenal (i.d.) or intrarectal (i.r.) dosing of SB was made after the i.v. and i.p. dosing, and the AUC's and the residual amount in the loop were obtained to estimate the parameters. The results of the i.d. and i.r. dosing were as follows; for the extent of bioavailability (EBA), 7.7 +/- 1.5% and 14.5 +/- 2.3%, for the fraction of dose absorbed (fa), 93.9 +/- 3.7% and 33.8 +/- 3.3%, and for the fraction of absorbed SB which avoids first-pass-effects (F), 8.4 +/- 1.9% and 43.0 +/- 6.0% (mean +/- S. E., n = 4). Consequently, SB dosed i.d. was absorbed completely, and received first-pass-metabolism in the mucosa (about 20%) and then in the liver (about 90%), which caused the low bioavailability. While, in i.r. dosing, SB absorption was poor. However, higher bioavailability was obtained owing to about 40% of rectal venous blood flow which bypasses the liver and negligible first-pass-metabolism in the mucosa (about 4%).
    No preview · Article · Nov 1993 · Yakugaku zasshi journal of the Pharmaceutical Society of Japan
  • N Kurosawa · E Owada · A Kato · K Bando · K Ito · S Kurosawa
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    ABSTRACT: In order to evaluate rectal administration of salbutamol (SB), five healthy volunteers were dosed orally and rectally with racemic SB (0.1 mg/kg) solution. Compared with the oral SB, the rectal SB gave significantly higher serum SB concentration immediately after dosing but slightly lower levels in the elimination phase. The Cmax following rectal administration was 17.9 ng/ml (17.0 ng/ml for oral administration), the tmax 0.67 h (1.5 h for oral administration) and the AUC 98.2 ng/ml/h (100 ng/ml/h for oral administration). Heart rate also rose more rapidly to a maximum of 70% above baseline values after rectal dosing. The rate continued to be twice larger than after oral dosing for up to 5 h. The concentration versus response curves indicated that rectal SB was more effective than oral SB at increasing heart rate at the same SB concentration in serum. A plausible explanation for this phenomenon might be a difference in the stereo-selective first-pass metabolism of the two enantiomers. Therefore, the rectal dose of SB administered as a suppository for prophylactic treatment of asthma should be lower than that used orally.
    No preview · Article · May 1993 · Journal of Clinical Pharmacy and Therapeutics
  • N Kurosawa · S Morishima · E Owada · K Ito
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    ABSTRACT: In order to obtain a basic knowledge for developing the rectal dosage form of salbutamol (SB), a comparison of the bioavailability was made between oral and rectal administrations. After the intravenous, oral and rectal dosing of SB solution in rabbits, SB and its glucuronide (SBG) in plasma and urine were determined. The bioavailability estimated by the area under the blood concentration-time curve (AUC) of SB from 0 to 9 h after oral and rectal administrations were 1.1 +/- 0.5% and 7.8 +/- 2.2% (mean +/- S. E., n = 5), respectively. Percent of dose excreted in urine as total SB (SB+SBG) 10 h after oral and rectal administrations were 77.3 +/- 3.82% and 9.80 +/- 0.15% (mean +/- S. E., n = 3), respectively, which indicating relatively good oral and poor rectal SB absorption. A partial avoidance of first-pass-effects might contribute to higher bioavailability after the rectal administration.
    No preview · Article · May 1993 · Yakugaku zasshi journal of the Pharmaceutical Society of Japan
  • J Sato · H Nakata · E Owada · T Kikuta · M Umetsu · K Ito
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    ABSTRACT: The influence of usual multiple ingestions of dietary caffeine on oral single-dose pharmacokinetics of theophylline has been investigated in 6 healthy male subjects. The subjects consumed 2 to 7 cups of regular instant coffee during the 24 h study period. Their mean serum concentrations of caffeine varied from 1.2 to 3.1 mg/l. After their usual intake of dietary caffeine, the serum concentrations of theophylline from 3 to 24 h after administration were significantly higher than after deprivation of dietary caffeine. The apparent elimination of theophylline half-life was prolonged from 6.3 (0.61) h (mean with (SEM)) to 8.3 (0.47) h (32% increase, P<0.01) and the total body clearance was reduced from 55.0 (1.31) ml·h−1·kg−1 to 42.5 (2.63) ml·h−1·kg−1 (23% decrase, P<0.001). Saturation of theophylline metabolism and/or competition between theophylline and caffeine metabolism in addition to theophylline derived from caffeine may be the cause of the delayed elimination of theophylline. The present study has indicated that a significant reduction in theophylline metabolism may be caused by a conventional intake of dietary caffeine. In bronchodilator therapy with theophylline, therefore, the daily consumption of caffeine should be taken into consideration.
    No preview · Article · Feb 1993 · European Journal of Clinical Pharmacology
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    ABSTRACT: Effect of repetitive administration of phenytoin (PHT) on the single-dose pharmacokinetics of primidone (PRM) was investigated in 3 healthy male subjects. The peak concentration of unchanged PRM was achieved at 12 and 8 h after the administration of PRM in the absence and the presence of PHT, respectively. The elimination half-life of PRM was decreased from 19.4 +/- 2.2 (mean +/- S.E.) to 10.2 +/- 5.1 h (p < 0.05) and the total body clearance was increased from 24.6 +/- 3.1 to 45.1 +/- 5.1 ml/h/kg (p < 0.01) in the presence of PHT. No significant change was observed for the apparent volume of distribution between the two treatments. In the absence of PHT, the measurable amount (> or = 0.1 mumol/l) of phenobarbital (PB) and phenylethylmalonamide (PEMA) did not appear in the serum until 5.3 and 1.3 h after the PRM administration, and the peak concentrations of PB and PEMA were achieved at 52 and 36 h, but the concentrations of both metabolites were very low (PB 1.3 mumol/l; PEMA 1.7 mumol/l). In the presence of PHT, within 0.8 and 0.5 h after the administration of PRM, the derived PB and PEMA appeared in the serum. About a 6-fold increase in the peak concentrations of both the metabolites were observed (PB 8.2 mumol/l; PEMA 11.0 mumol/l). No significant changes were observed for the elimination half-lives of both PB and PEMA in the absence and presence of PHT.(ABSTRACT TRUNCATED AT 250 WORDS)
    No preview · Article · Oct 1992 · Journal of pharmacobio-dynamics
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    ABSTRACT: The pharmacokinetics of diltiazem (DTZ) was investigated in seven control subjects with normal liver function and in seven patients with liver cirrhosis. After long-term oral administration of diltiazem, 30 or 60 mg thrice daily, serum levels of DTZ and its active metabolites, deacetyl DTZ (DAD) and N-demethyl DTZ (DMD), were determined by high performance liquid chromatography. The mean peak serum concentrations (nmol/L) in control patients were 280 for DTZ, 58 for DAD and 101 for DMD. In cirrhotic patients, the serum DTZ tended to increase and the DAD increased (p less than 0.05), while the DMD decreased (p less than 0.05) compared with that of the control (335 for DTZ, 133 for DAD and 77 for DMD, nmol/L). Pharmacokinetic analysis using a one-compartment model revealed no change in the absorption, but a decrease in the elimination for cirrhotic patients (t 1/2; 5.3 to 7.2 h, p less than 0.1). The elimination rate constant correlated with some biochemical indices for hepatocyte function. These results may be explained by the impaired oxidative metabolism of diltiazem in liver cirrhosis.
    No preview · Article · Feb 1990 · International journal of clinical pharmacology research

  • No preview · Article · Sep 1989 · Journal of Chromatography A

  • No preview · Article · May 1987 · Journal of Pediatrics
  • S Kurosawa · N Kurosawa · E Owada · N Matsuhashi · K Ito
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    ABSTRACT: The haemodynamic effects and pharmacokinetics of nifedipine suppositories, used mainly for hypertensive emergencies, were studied in 10 severely hypertensive patients. Following rectal administration, significant hypotensive effects occurred after 0.5 h and lasted until 7 h after administration. The mean (+/- SE) maximum decreases in systolic and diastolic blood pressures 1.5 h after administration were: systolic, 61.8 +/- 7.9 mmHg (P less than 0.001); and diastolic, 30.8 +/- 4.0 mmHg (P less than 0.001). No serious side-effects were reported and heart rate did not change significantly. Mean nifedipine concentration in the blood peaked at 52.4 ng/ml, 1 h after administration and, after 7 h, was still 14.3 ng/ml which is higher than the minimum plasma concentration required for hypotensive effects to occur. There was a close correlation between nifedipine concentration in the blood and hypotensive effects. These results indicate that rectal administration of nifedipine should be regarded as a useful alternative treatment in hypertensive emergencies.
    No preview · Article · Jan 1987 · The Journal of international medical research
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    ABSTRACT: A sensitive method for determination of serum primidone (PRM) and its active metabolites, phenobarbital (PB) and phenylethylmalonamide (PEMA), was established to clarify the time-courses of serum PRM, PB and PEMA after a single oral administration of PRM to man. In this method, the serum was acidified and extracted with a mixture of chlorofrom-isopropanol (70 : 30).An aliquot of the organic phase was treated with 0.1 N sodium hydroxide to separate PRM and PEMA from PB and interfering substances. Then PRM and PEMA were simultaneously determined by reversed-phase high-performance liquid chromatography (HPLC) using a mixture of acetonitrile-water (12 : 88) as a mobile phase. PB was also determined by HPLC using a mixture of acetonitrile-phosphate buffer (19 : 81, pH 4.5) as a mobile phase after extraction with chloroform from the acidified aqueous alkaline phase. Sufficient accuracy and precision to determine submicrogram levels (50-1000 ng/ml) of serum PRM, PB and PEMA were obtained. By this method, serum PRM and its active metabolites were successfully measured for at least 5 d after a single 600 mg dose of PRM to a human subject.
    No preview · Article · Aug 1986 · CHEMICAL & PHARMACEUTICAL BULLETIN
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    ABSTRACT: Nifedipine rectal suppositories were prepared with polyethylene glycol as a base as a treatment for hypertensive emergency. The suppository which contained 10 mg of nifedipine had adequate physical characteristics and nifedipine stability for practical use. Bioavailability of the suppository was compared to that of an oral capsule (10 mg of nifedipine content) in healthy subjects. The mean nifedipine plasma concentration curve following rectal administration showed slightly delayed absorption as compared to the oral administration. However, there was no significant difference in the AUC from 0 to 7 h between the suppository and the capsule, which suggested the same extent of bioavailability for both dosage forms. A hypotensive effect of the nifedipine suppository for the subjects was observed 30 min after the administration and the effect was more definite and more prolonged compared to the oral capsule.
    No preview · Article · Nov 1985 · International Journal of Pharmaceutics