Biomedical subjects

Ryuichi Hasegawa

Publications and source records attributed to Ryuichi Hasegawa.

At least 19 recordsLinked to original sources

PubMed2007

Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism.

PURPOSE: Gemcitabine is rapidly metabolized to its inactive metabolite, 2',2'-difluorodeoxyuridine (dFdU), by cytidine deaminase (CDA). We previously reported that a patient with homozygous 208A alleles of CDA showed severe adverse reactions with an increase in gemcitabine plasma level. This study extended the investigation of the effects of CDA genetic polymorphisms on gemcitabine pharmacokinetics and toxicities. PATIENTS AND METHODS: Genotyping of CDA was performed by a direct sequencing of DNA obtained from the peripheral blood of Japanese gemcitabine-naïve cancer patients (n = 256). The patients recruited to the association study received a 30-minute intravenous infusion of gemcitabine at a dose of either 800 or 1,000 mg/m2, and eight blood samples were periodically collected (n = 250). Plasma levels of gemcitabine and dFdU were measured by high-performance liquid chromatography. Plasma CDA activities toward cytidine and gemcitabine were also measured (n = 121). RESULTS: Twenty-six genetic variations, including 14 novel ones and two known nonsynonymous single nucleotide polymorphisms (SNPs), were detected. Haplotypes harboring the nonsynonymous SNPs 79A>C (Lys27Gln) and 208G>A (Ala70Thr) were designated *2 and *3, respectively. The allelic frequencies of the two SNPs were 0.207 and 0.037, respectively. Pharmacokinetic parameters of gemcitabine and plasma CDA activities significantly depended on the number of haplotype *3. Haplotype *3 was also associated with increased incidences of grade 3 or higher neutropenia in the patients who were coadministered fluorouracil, cisplatin, or carboplatin. Haplotype *2 showed no significant effect on gemcitabine pharmacokinetics. CONCLUSION: Haplotype *3 harboring a nonsynonymous SNP, 208G>A (Ala70Thr), decreased clearance of gemcitabine, and increased incidences of neutropenia when patients were coadministered platinum-containing drugs or fluorouracil.

Adult↗

PubMed2006

Identification of regulatory sites in the human PXR (NR1I2) promoter region.

The human pregnane X receptor (hPXR, NR1I2) is a member of the nuclear receptor superfamily and a key regulator of genes encoding several major cytochrome P450 enzymes and transporters. However, the transcriptional regulation of hPXR itself remains unclear. We recently reported significant diversity in the 5' region of human hepatic PXR transcripts and identified the major transcription initiation site. Here, we investigate the transcriptional regulatory sites in the hPXR 5'-flanking region. Luciferase reporter constructs containing various lengths of 5'-flanking region, up to 10.5 kb upstream of the major transcription initiation site, were assessed for promoter activity in HepG2 cells. We mapped the minimal essential region for promoter activity to a 160 bp region upstream of the transcription initiation site, an area that also showed nuclear protein binding. Constructs with mutations introduced into these protein-binding sites demonstrated reduced promoter activity concomitant with reduced DNA-protein binding activity. hPXR promoter activity was observed in HepG2 cells but not in HeLa cells. Likewise, nuclear protein binding to promoter elements was also observed in HepG2 but not HeLa cells. The present study provides basic information on the transcriptional regulation of hPXR and may help elucidate the regulatory mechanisms of hPXR target genes.

5' Flanking Region↗

PubMed2006

Four novel defective alleles and comprehensive haplotype analysis of CYP2C9 in Japanese.

Genetic variations in cytochrome P450 2C9 (CYP2C9) are known to contribute to interindividual and interethnic variability in response to clinical drugs such as warfarin. In the present study, CYP2C9 from 263 Japanese subjects was resequenced, resulting in the discovery of 62 variations including 32 novel ones. In addition to the two known non-synonymous single nucleotide polymorphisms (SNPs), Ile359Leu (*3; allele frequency=0.030) and Leu90Pro (*13; 0.002), seven novel non-synonymous SNPs, Leu17Ile (0.002), Lys118ArgfsX9 (*25; 0.002), Thr130Arg (*26; 0.002), Arg150Leu (*27; 0.004), Gln214Leu (*28; 0.002), Pro279Thr (*29; 0.002) and Ala477Thr (*30; 0.002), were found. Functional characterization of novel alleles using a mammalian cell expression system in vitro revealed that *25 was a null allele and that *26, *28 and *30 were defective alleles. The *26 product showed a 90% decrease in the Vmax value but little change in the Km value towards diclofenac. Both *28 and *30 products showed two-fold higher Km values and three-fold lower Vmax values than the *1 allele, suggesting the importance of Gln214 and Ala477 for substrate recognition. Linkage disequilibrium and haplotype analyses were performed using the detected variations. Only five haplotypes (frequency >0.02) accounted for most (>87%) of the inferred haplotypes, and they were closely associated with the haplotypes of CYP2C19 in Japanese. Although the haplotype structure of CYP2C9 was rather simple in Japanese, the haplotype distribution was quite different from those previously reported in Caucasians and Africans. Taken together, novel defective alleles and detailed haplotype structures would be useful for determining metabolic phenotypes of CYP2C9 substrate drugs in Japanese and probably Asians.

Alleles↗

PubMed2006

Susceptibility of newborn rats to 3-ethylphenol and 4-ethylphenol compared with that of young rats.

Newborn rat studies were conducted with oral administration of 3-ethylphenol (3EP) and 4-ethylphenol (4EP) on postnatal days (PND) 4-21 to allow comparison of no observed adverse effect level (NOAEL) and unequivocally toxic level (UETL) with those from 28-day studies of young rats starting at 5-6 weeks of age. In the newborn rat studies, slightly lowered body weight was observed after 3EP treatment, and deaths, hypoactivity, Straub tail, deep respiration and delayed righting reflex were clearly observed after 4EP treatment. In the young rat studies, salivation, staggering gait, changes in the liver including high values of liver weight and alanine aminotransferase or total cholesterol and the lesions in the forestomach were clearly observed after 3EP and 4EP treatments. NOAELs of 3EP and 4EP in the newborn rat studies appeared to be almost 3 times lower than those in the young rat studies. As a clear toxicity of 3EP was not observed in newborn rats, UETLs were not established for 3EP. Regarding 4EP, UETL of young rats was 4-5 times higher than that of newborn rats. In conclusion, newborn rats were 3-5 times more susceptible to 3EP and 4EP than young rats.

Administration, Oral↗

PubMed2006

Semi-quantitative immunohistochemical analysis of male rat-specific alpha2u-globulin accumulation for chemical toxicity evaluation.

We purified male rat urinary alpha(2u)-globulin, prepared the antibody in rabbits, and improved an immunohistochemical detection method using this antibody for male rat-specific alpha(2u)-globulin accumulation appearing as hyaline droplets in the kidneys. Our prepared antibody reacted specifically with alpha(2u)-globulin in both immunohistochemical and Western blotting analyses, furthermore, and the graded immuno-reactivities on the slide were well associated with computational image analyzing results. Using this method, we retrospectively analyzed the renal sections from the toxicity studies of 12 nephrotoxic chemicals, which had already been conducted under the Japanese Existing Chemicals Survey Program. We demonstrated that the hyaline droplets induced by treatment with 10 chemicals (1,4-dibromobenzene, dicyclopentadiene, 3,4-dimethylaniline, 1,4-dicyanobenzene, tetrahydrothiophene-1,1-dioxide, 1,3-dicyanobenzene, acenaphthene, 3,4-dichloro-1-butene, 3a,4,7,7a-tetrahydro-1H-indene and 3,5,5-trimethylhexan-1-ol) were directly associated with alpha(2u)-globulin accumulation. This immunohistochemical method is convenient for applying, even retrospectively, paraffin sections from general toxicity studies and could be useful for qualifying male rat-specific hyaline droplets consisting of alpha(2u)-globulin and renal risk in humans.

Alpha-Globulins↗

PubMed2006

[Case of acute respiratory distress syndrome in which high-frequency oscillatory ventilation (HFOV) was effective for the management of severe hypoxemia].

A 69-year-old man was admitted to our hospital because of acute prostatitis. After admission he produced bloody sputum and chest radiograph showed bilateral infiltration of the upper lung fields. The fraction of neutrophils in the bronchoalveolar lavage fluid was 15.6%, lymphocytes were 33.6%, eosinophils were 26.6% and macrophages were 23.6%. No special findings were observed in the lung tissue obtained by transbronchial lung biopsy. After admission, he displayed acute respiratory distress syndrome with severe hypoxemia as dyspnea gradually progressed. We commenced treatment with high-dose pulse methylprednisolone and neutrophil elastase inhibitor under mechanical ventilation. Because severe hypoxemia was unresolved, HFOV was initiated on the 8th hospital day. His respiratory condition rapidly improved during HFOV. On the 17th hospital day, he was weaned from mechanical ventilation. HFOV seem to be safe and effective for patients with severe ARDS who failed conventional ventilation support.

Aged↗

PubMed2005

Effect of CYP2C9 genetic polymorphisms on the efficacy and pharmacokinetics of glimepiride in subjects with type 2 diabetes.

Glimepiride, a sulfonylurea hypoglycemic agent, is metabolized by cytochrome P450 2C9 (CYP2C9) which is known to have genetic polymorphisms. To examine the effects of CYP2C9 genetic polymorphisms on the safety and efficacy of glimepiride in patients with type 2 diabetes, the responses to the glimepiride were measured in Japanese type 2 diabetic patients with the different CYP2C9 genotype. The reduction in the HbA(1c) was significantly larger (P<0.05) among the CYP2C9*1/*3 subjects than among the CYP2C9*1/*1 subjects. The long-term observations of 2 patients with a CYP2C9*1/*3 suggested that subjects with a CYP2C9*1/*3 respond well to glimepiride during the initial phase of treatment, but 1 patient have shown the weight gain over the long-term treatment. The pharmacokinetic study showed that the area under the concentration-time curve for glimepiride in the CYP2C9*1/*3 subjects was approximately 2.5-fold higher than that of the CYP2C9*1/*1 subjects. The intrinsic clearance of glimepiride by the CYP2C9*3 enzyme was lower than that by the CYP2C9*1 enzyme. These results suggested that the lower hydroxylation activity of glimepiride in the subject with type 2 diabetes and CYP2C9*1/*3 led to a marked elevation in the plasma concentrations of glimepiride and a stronger pharmacological effect of glimepiride.

Adult↗

PubMed2005

Comparison of information on the pharmacokinetic interactions of Ca antagonists in the package inserts from three countries (Japan, USA and UK).

OBJECTIVE: Ca antagonists are one of the most popular classes of drugs used to treat hypertension and angina. These drugs may interact with either CYP3A4 or MDR-1 substrates, with the degree of interaction differing with each drug. We carried out a literature search to examine and compare the extent to which crucial pharmacokinetic (PK) information is included in package inserts (PIs) in Japan, USA and the UK. METHODS: A MEDLINE search from 1966 to November 2004 was undertaken with the aim of identifying studies on clinical PK drug interactions between seven Ca antagonists that are available in three countries and three CYP3A4 inhibitors (erythromycin, itraconazole and cimetidine), a CYP3A4 inhibitory food, grapefruit juice (GFJ) and the MDR-1 substrate, digoxin. The current PIs for Ca antagonists were obtained from the website of the regulatory authorities or the electronic Medicines Compendium. RESULTS: Of all possible combinations of seven Ca antagonists with three CYP3A4 inhibitor drugs, drug interaction information was available in the literature on nine combinations: Seven of these were listed in the USA PIs, two in the UK PIs, and none in the Japanese PIs. Interaction studies with GFJ were reported for every Ca antagonist; PIs in the USA provided quantitative data for four of these interactions, whereas UK PIs provided quantitative data for only one of the interactions and Japanese PIs provided no quantitative information. The PK data of co-medication of digoxin with Ca antagonists have been reported for every Ca antagonists. The USA PIs provided quantitative data for five Ca antagonists, whereas the UK PIs provided quantitative data for three Ca antagonists and Japanese PIs provided no quantitative data. CONCLUSION: The literature search revealed that PIs in the USA provided a great deal of quantitative information on PK interactions between Ca antagonists and other drugs or GFJ. In contrast, PIs in the UK and Japan did not provide sufficient information. We conclude that crucial quantitative information on these drug interactions should be incorporated in PIs, especially in Japan and the UK, as a means of assisting healthcare providers.

Calcium Channel Blockers↗

PubMed2005

Functional analysis of four naturally occurring variants of human constitutive androstane receptor.

The human constitutive androstane receptor (CAR, NR1I3) is a member of the orphan nuclear receptor superfamily that plays an important role in the control of drug metabolism and disposition. In this study, we sequenced all the coding exons of the NR1I3 gene for 334 Japanese subjects. We identified three novel single nucleotide polymorphisms (SNPs) that induce non-synonymous alterations of amino acids (His246Arg, Leu308Pro, and Asn323Ser) residing in the ligand-binding domain of CAR, in addition to the Val133Gly variant, which was another CAR variant identified in our previous study. We performed functional analysis of these four naturally occurring CAR variants in COS-7 cells using a CYP3A4 promoter/enhancer reporter gene that includes the CAR responsive elements. The His246Arg variant caused marked reductions in both transactivation of the reporter gene and in the response to 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO), which is a human CAR-specific agonist. The transactivation ability of the Leu308Pro variant was also significantly decreased, but its responsiveness to CITCO was not abrogated. The transactivation ability and CITCO response of the Val133Gly and Asn323Ser variants did not change as compared to the wild-type CAR. These data suggest that the His246Arg and Leu308Pro variants, especially His246Arg, may influence the expression of drug-metabolizing enzymes and transporters that are transactivated by CAR.

Animals↗

PubMed2005

Severe drug toxicity associated with a single-nucleotide polymorphism of the cytidine deaminase gene in a Japanese cancer patient treated with gemcitabine plus cisplatin.

PURPOSE: We investigated single-nucleotide polymorphisms of the cytidine deaminase gene (CDA), which encodes an enzyme that metabolizes gemcitabine, to clarify the relationship between the single-nucleotide polymorphism 208G>A and the pharmacokinetics and toxicity of gemcitabine in cancer patients treated with gemcitabine plus cisplatin. EXPERIMENTAL DESIGN: Six Japanese cancer patients treated with gemcitabine plus cisplatin were examined. Plasma gemcitabine and its metabolite 2',2'-difluorodeoxyuridine were measured using an high-performance liquid chromatography method, and the CDA genotypes were determined with DNA sequencing. RESULTS: One patient, a 45-year-old man with pancreatic carcinoma, showed severe hematologic and nonhematologic toxicities during the first course of chemotherapy with gemcitabine and cisplatin. The area under the concentration-time curve value of gemcitabine in this patient (54.54 microg hour/mL) was five times higher than the average value for five other patients (10.88 microg hour/mL) treated with gemcitabine plus cisplatin. The area under the concentration-time curve of 2',2'-difluorodeoxyuridine in this patient (41.58 microg hour/mL) was less than the half of the average value of the five patients (106.13 microg hour/mL). This patient was found to be homozygous for 208A (Thr70) in the CDA gene, whereas the other patients were homozygous for 208G (Ala70). CONCLUSION: Homozygous 208G>A alteration in CDA might have caused the severe drug toxicity experienced by a Japanese cancer patient treated with gemcitabine plus cisplatin.

Aged↗

PubMed2005

Haplotype structures of EPHX1 and their effects on the metabolism of carbamazepine-10,11-epoxide in Japanese epileptic patients.

OBJECTIVE: Microsomal epoxide hydrolase (mEH) is an enzyme that detoxifies reactive epoxides and catalyzes the biotransformation of carbamazepine-10,11-epoxide (CBZ-epoxide) to carbamazepine-10,11-diol (CBZ-diol). Utilizing single nucleotide polymorphisms (SNPs) of the EPHX1 gene encoding mEH, we identified the haplotypes of EPHX1 blocks and investigated the association between the block haplotypes and CBZ-epoxide metabolism. METHODS: SNPs of EPHX1 were analyzed by means of polymerase chain reaction amplification and DNA sequencing using DNA extracted from the blood leukocytes of 96 Japanese epileptic patients, including 58 carbamazepine-administered patients. The plasma concentrations of CBZ and its four metabolites were determined using high-performance liquid chromatography. RESULTS: From sequencing all 9 exons and their surrounding introns, 29 SNPs were found in EPHX1. The SNPs were separated into three blocks on the basis of linkage disequilibrium, and the block haplotype combinations (diplotypes) were assigned. Using plasma CBZ-diol/CBZ-epoxide ratios (diol/epoxide ratios) indicative of the mEH activity, the effects of the diplotypes in each EPHX1 block were analyzed on CBZ-epoxide metabolism. In block 2, the diol/epoxide ratios increased significantly depending on the number of haplotype *2 bearing Y113H (P=0.0241). In block 3, the ratios decreased depending on the number of haplotype *2 bearing H139R (P=0.0351). Also, an increasing effect of a *1 subtype, *1c, was observed on the ratio. CONCLUSION: These results show that some EPHX1 haplotypes are associated with altered CBZ-epoxide metabolism. This is the first report on the haplotype structures of EPHX1 and their potential in vivo effects.

Adolescent↗

PubMed2005

5' diversity of human hepatic PXR (NR1I2) transcripts and identification of the major transcription initiation site.

The human pregnane X receptor (PXR) is a crucial regulator of the genes encoding several major cytochrome P450 enzymes and transporters, such as CYP3A4 and MDR1, but its own transcriptional regulation remains unclear. To elucidate the transcriptional mechanisms of human PXR gene, we first endeavored to identify the transcription initiation site of human PXR using 5'-RACE. Five types of 5'-variable transcripts (a, b, c, d, and e) with common exon 2 sequence were found, and comparison of these sequences with the genomic sequence suggested that their 5' diversity is derived from initiation by alternative promoters and alternative splicing. None of the exons found in our study contain any new in-frame coding regions. Newly identified introns IVS-a and IVS-b were found to have CT-AC splice sites that do not follow the GT-AG rule of conventional donor and acceptor splice sites. Of the five types of 5' variable transcripts identified, RT-PCR showed that type-a was the major transcript type. Four transcription initiation sites (A-D) for type-a transcript were identified by 5'-RACE using GeneRacer RACE Ready cDNA (human liver) constructed by the oligo-capping method. Putative TATA boxes were located approximately 30 bp upstream from the transcriptional start sites of the major transcript (C) and the longest minor transcript (A) expressed in the human liver. These results indicate that the initiation of transcription of human PXR is more complex than previously reported.

5' Untranslated Regions↗

PubMed2005

Comparative susceptibility of newborn and young rats to six industrial chemicals.

To elucidate the comparative susceptibility of newborn rats to chemicals, newborn and young animals were administered six industrial chemicals by gavage from postnatal days (PND) 4 to 21, and for 28 days starting at 5-6 weeks of age respectively, under the same experimental conditions as far as possible. As two new toxicity endpoints specific to this comparative analysis, presumed no-observed-adverse-effect-levels (pNOAELs) were estimated based on results of both main and dose-finding studies, and presumed unequivocally toxic levels (pUETLs) were also decided. pNOAELs for newborn and young rats were 40 and 200 for 2-chlorophenol, 100 and 100 for 4-chlorophenol, 30 and 100 for p-(alpha,alpha-dimethylbenzyl) phenol, 100 and 40 for (hydroxyphenyl)methyl phenol, 60 and 12 for trityl chloride, and 100 and 300 mg/kg/day for 1,3,5-trihydroxybenezene, respectively. To determine pUETLs, dose ranges were adopted in several cases because of the limited results of experimental doses. Values for newborn and young rats were thus estimated as 200-250 and 1000 for 2-chlorophenol, 300 and 500 for 4-chlorophenol, 300 and 700-800 for p-(alpha,alpha-dimethylbenzyl) phenol, 140-160 and 1000 for (hydroxyphenyl)methyl phenol, 400-500 and 300 for trityl chloride, and 500 and 1000 mg/kg/day for 1,3,5-trihydroxybenzene, respectively. In most cases, newborn rats were 2-5 times more susceptible than young rats in terms of both the pNOAEL and the pUETL. An exception was that young rats were clearly more susceptible than their newborn counterparts for trityl chloride.

Animals↗

PubMed2005

Elevated susceptibility of newborn as compared with young rats to 2-tert-butylphenol and 2,4-di-tert-butylphenol toxicity.

In order to determine the susceptibility of newborn rats to 2-tert-butylphenol (2TBP) and 2,4-di-tert-butylphenol (DTBP) toxicity, studies were conducted with oral administration from postnatal days (PND) 4 to 21 and the findings were compared with results for young rats exposed from 5 or 6 weeks of age for 28 days. In the newborn rats, specific effects on physical and sexual development and reflex ontogeny were not observed. While there were no clear differences in toxicological profiles between newborn and young rats, the no-observed-adverse-effect levels (NOAELs) differed markedly. For 2TBP, clinical signs such as ataxic gait, decrease in locomotor activity and effects on liver, such as increase in organ weight, were observed and the NOAELs were concluded to be 20 and 100 mg/kg/day in newborn and young rats, respectively. Based on hepatic and renal toxicity (histopathological changes and increase in organ weight with blood biochemical changes), the respective NOAELs for DTBP were concluded to be 5 and 20 mg/kg/day. Therefore, the susceptibility of newborn rats to 2TBP and DTBP was found to be 4-5 times higher than that of young rats.

Age Factors↗

PubMed2005

Susceptibility of newborn rats to hepatotoxicity of 1,3-dibromopropane and 1,1,2,2-tetrabromoethane, compared with young rats.

Newborn rat studies were conducted with oral administration of 1,3-dibromopropane (DBP) and 1,1,2,2-tetrabromoethane (TBE) from postnatal Days 4 to 21 to allow comparison of NOAELs and unequivocally toxic levels with those from 28-day young rat studies starting at 5-6 weeks of age. The unequivocally toxic level was estimated by our specified criteria, requiring simultaneous change of organ weights, histopathology, some biochemical parameters and body weights, because in this study only hypertrophy of hepatocytes was observed as a major histopathological change. DBP caused centrilobular hypertrophy of hepatocytes with alteration in biochemical parameters, as well as lowering of body weights, regardless of sex, in both newborn and young rats. NOAELs and unequivocally toxic levels were considered to be 50 and 150 mg/kg/day in newborn rats and 10 and 250 mg/kg/day in young rats, respectively. In the newborn rat study of TBE, some hepatic effects observed at the top dose of 50 mg/kg were not considered adverse because of the lack of histopathological changes. Significant lowering of body weight was noted at 200 mg/kg in the dose-finding study but histopathological data were not available. In the young rat study, there was no definite toxicity at 6 mg/kg and hypertrophic changes in liver and thyroids without body weight change occurred at 200 mg/kg. There were no clear sex differences in both the newborn and young rat studies. NOAELs were considered to be 50 and 6 mg/kg/day in newborn and young rats, respectively, but unequivocally toxic levels for both rats could not be estimated. Abnormalities of external and sexual development and reflex ontogeny in the newborn were not observed with either chemical. Based on these results, it can be concluded that the target organ of DBP and TBE is the liver in both newborn and young rats, and that while the doses at which toxic signs began to appear are higher in newborn rats, those causing clear toxicity may be paradoxically lower in the newborn case.

Age Factors↗

PubMed2005

Genetic variations and haplotypes of CYP2C19 in a Japanese population.

Forty-eight single nucleotide variations, including 27 novel ones, were found in the 5'- regulatory region, all of the exons and their surrounding introns of CYP2C19 in 253 Japanese subjects (134 diabetic patients and 119 healthy volunteers). Identified novel variations were as follows: -2772G>A, 2767_-2760delGGTGAACA, -2720T>C, -2547delG, -2545G>T, -2545_-2544 delGC, and -2040C>T in the enhancer region; -778C>T, -777G>A, -529G>C, -189C>A, and -185A>G in the promoter region; 151A>G (S51G), 481G>C (A161P), 986G>A (R329H), 1078G>A (D360N), and 1119C>T (D373D) in the exons, and IVS1+128T>A, IVS3+163G>A, IVS4+271A>G, IVS5-49A>G, IVS6-210C>T, IVS6-196T>A, IVS6-32T>A, IVS7+84G>A, IVS7-174C>T, and IVS8+64C>T in the introns. Since we found no significant differences in the variation frequencies between healthy volunteers and diabetic patients, the data for all subjects were treated as one group in further analysis. The allele frequencies were 0.265 for IVS6-196T>A, 0.045 for -2772G>A and -2720T>C, 0.024 for -2040C>T, 0.014 for IVS7-174C>T, 0.010 for -529G>C, 0.006 for IVS1+128T>A and 481G>C (A161P), 0.004 for -2767_-2760delGGTGAACA and IVS6-210C>T, and 0.002 for the other 17 variations. In addition, the two known nonsynonymous single nucleotide polymorphisms, 681G>A (splicing defect, (*)2 allele) and 636G>A (W212X; (*)3 allele) were detected at 0.267 and 0.128 frequencies, respectively. No variation was detected in the known binding sites for constitutive androstane receptor and glucocorticoid receptor. Linkage disequilibrium analysis showed several close linkages of variations throughout the gene. By using the variations, thirty-one haplotypes of CYP2C19 and their frequencies were estimated. Our results would provide fundamental and useful information for genotyping CYP2C19 in the Japanese and probably other Asian populations.

Aryl Hydrocarbon Hydroxylases↗

PubMed2005

Undesirable effects of citrus juice on the pharmacokinetics of drugs: focus on recent studies.

It is well known that intake of grapefruit juice affects the pharmacokinetics of various kinds of drugs. It has been reported that other citrus juices also interact with certain drugs. To re-evaluate citrus juice-drug interactions based on currently available evidence, a literature search was conducted for new and updated information since the grapefruit juice-drug interaction was last reviewed in 1998. MEDLINE (1998-October 2004) was accessed and more than 200 reports were found. The effects of grapefruit juice ingestion on the pharmacokinetics of orally administered drugs have been reported for 40 drugs since the reviews published in 1998. Increases in either area under the concentration-time curve (AUC) or maximum plasma concentration (C(max)) were found with 34 of these, the major mechanism being considered to be inactivation of intestinal cytochrome P450 3A4, a so-called mechanism-based inhibition. Although recent reports point to the inhibitory effects of grapefruit juice on the function of P-glycoprotein, which transports substrates from enterocytes back into the lumen, the contribution to the bioavailability of drugs that are substrates of P-glycoprotein has not been established yet. Dramatic decreases in AUC and C(max) for two drugs in association with grapefruit juice ingestion has been reported and, in these cases, inhibitory effects on organic anion transporting polypeptide, which mediates absorption from the intestinal lumen to enterocytes, might be involved. Other citrus juices such as Seville (sour) orange juice and commonly ingested varieties of orange juice also showed significant effects on the AUC and C(max) of some drugs. Although the situation is complex and uncertainties remain, we recommend that patients avoid citrus juice intake while taking medications and that healthcare providers advise against citrus juice intake in this setting until any interactions with subject drugs can be clarified in clinical studies.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2005

[Improvement of package insert CYP information for prescription drugs marketed in Japan].

In clinical practice, one drug is frequently used in combination with one or more other drugs, rather than as a sole regimen, and therefore healthcare providers need to carefully consider drug interactions. As mechanisms of drug interactions, metabolic enzymes of drugs are seen as one of the most likely interactive sites, where a majority of drugs are metabolized by cytochrome P450 (CYP). For this reason, providing appropriate information on CYP in package inserts is of grave importance. In fact, the package insert is the primary tool for supplying information on drugs to healthcare providers. The present study was designed to determine how many package inserts of prescription drugs marketed in Japan were providing CYP information. We searched the April 2003 version of "Drugs in Japan DB," which listed 2,022 prescription drugs, and found that only 239 package inserts (11.8%) mentioned CYP information and that only 194 (9.6%) specified CYP isozymes. To assess the improvement of package inserts, we searched "Drugs in Japan DB" from the January 2000 version to the April 2003 version. We found that CYP information had increased year by year (eg, 7.8-11.8% annually). For newly approved drugs, an analysis of the relationship between approval year and CYP information in package inserts (April 2003 version) revealed that recently approved drugs had more CYP information (eg, 45.5-51.3% of drugs in 1999-2002, compared to 6.8-26.1% in 1991-1996). A search for regulatory review documents for new drugs approved from 1999 to 2002 suggested that this recent improvement could be related to the increased number of studies identifying CYP isozymes involved in the metabolism or interaction with other drugs. Another reason for the recent improvement may be the fact that the guideline for package inserts for prescription drugs was revised in 1997, and the guidelines for drug interaction and pharmacokinetic studies were published between 1997 and 1999.

Cytochrome P-450 Enzyme System↗