著者

酒井 孝範 粟田 則男

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.8, no.2, pp.263-272, 1993-04-10 (Released:2007-03-29)

参考文献数

23

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The vagina is an important area of the reproductive tract. The vaginal route of administration of drugs may be a viable alternative to oral theraphy. But the vaginal preparations on the market are exclusively restricted to those are topically effective. Most of agents in vaginal preparations act directory on the vaginal membrane. Vaginal absorption is characterized by the avoidance of hepatic first pass effect, prolonged retention of the blood level and the variation throughout the reproductive cycle. In this minireview, the vaginal absorption of several drugs with low molecular weight is introduced from the standpoint of chemical structure, first pass effect and transport process. In addition, we discuss the vaginal absorption of prasterone sulfate(PS)in rats. PS is almost completely absorbed from the vagina. PS may be transported through vaginal membranes by both paracellular route and carriermediated process.

著者

久保田 隆廣 千葉 寛 伊賀 立二

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.16, no.2, pp.69-74, 2001 (Released:2007-03-29)

参考文献数

34

被引用文献数

2 4

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Approximately 1% of Orientals and 7 to 10% of Caucasians lack the activity of cytochrome P450 (CYP) 2D6, and these individuals are known as poor metabolizers (PM). On the other hand, approximately 4% of Caucasians are PM of CYP2C19, while its frequencies are 18 to 23% in Orientals. These differences in the frequencies of PM seen in the different ethnic populations are mainly due to the differences in the distribution frequency of variously defective alleles of CYP2D6 and 2C19. Recent progress in molecular biology of CYPs has enabled the mechanism of CYP polymorphism to be elucidated and the polymerase chain reaction was developed for its genotyping. Our previous studies showed that the frequencies of CYP2C19*2, *3, CYP2D6*2, *5, *10, *14, and CYP2C9*3 among the Japanese subjects were 28.7, 13.2, 12.9, 6.2, 38.6, 2.2 and 2.1%, respectively. In this review, we compared the frequencies of these mutant alleles of CYPs seen in the Japanese population with those reported previously for other ethnic populations.

著者

伊賀 立二

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.11, no.3, pp.309-314, 1996-06-30 (Released:2007-03-29)

参考文献数

4

被引用文献数

1 2

著者

Xiachu ZHANG Feng LIU Xin CHEN Xu ZHU Jack UETRECHT

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

Drug Metabolism and Pharmacokinetics (ISSN:13474367)

巻号頁・発行日

vol.26, no.1, pp.47-59, 2011 (Released:2011-03-03)

参考文献数

135

被引用文献数

39

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There is strong evidence that most idiosyncratic drug reactions (IDRs) are immune-mediated and are caused by reactive metabolites of a drug rather than by the drug itself. Several hypotheses have been proposed by which a drug could induce an immune response. The major hypotheses are the hapten hypothesis and the danger hypothesis; however, the characteristics and spectrum of IDRs are different with different drugs, and this likely reflects mechanistic differences; therefore, no one hypothesis is likely to explain all IDRs. Some IDRs appear to involve epigenetic effects, direct activation of antigen-presenting cells, or disturbing the normal balance of the immune system. It has been suggested that many cases of idiosyncratic liver injury are not immune-mediated, and other mechanisms such as mitochondrial injury may be involved. It is essential that any hypothesis be consistent with the clinical characteristics of the IDR. Although the characteristics of most idiosyncratic liver injury do not suggest that mitochondria are the major target, it is quite possible that milder mitochondrial injury could stimulate an immune-mediated reaction. The observation that IDRs can vary widely among different drugs and different patients is most easily explained by an immune mechanism in which the target of the immune response is different.

著者

Rongrong JIANG Satoshi YAMAORI Yasuka OKAMOTO Ikuo YAMAMOTO Kazuhito WATANABE

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

Drug Metabolism and Pharmacokinetics (ISSN:13474367)

巻号頁・発行日

vol.28, no.4, pp.332-338, 2013 (Released:2013-08-25)

参考文献数

49

被引用文献数

148

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The present study investigated the inhibitory effect of cannabidiol (CBD), a major constituent of marijuana, on the catalytic activity of cytochrome P450 2C19 (CYP2C19). (S)-Mephenytoin 4′-hydroxylase activities of human liver microsomes (HLMs) and recombinant CYP2C19 were inhibited by CBD in a concentration-dependent manner (IC50 = 8.70 and 2.51 µM, respectively). Omeprazole 5-hydroxylase and 3-O-methylfluorescein O-demethylase activities in recombinant CYP2C19 were also strongly inhibited by CBD (IC50 = 1.55 and 1.79 µM, respectively). Kinetic analysis for inhibition revealed that CBD showed a mixed-type inhibition against (S)-mephenytoin 4′-hydroxylation by recombinant CYP2C19. To clarify the structural requirements for CBD-mediated CYP2C19 inhibition, the effects of CBD-related compounds on CYP2C19 activity were examined. Olivetol inhibited the (S)-mephenytoin 4′-hydroxylase activity of recombinant CYP2C19 with the IC50 value of 15.3 µM, whereas d-limonene slightly inhibited the activity (IC50 > 50 µM). The inhibitory effect of CBD-2′-monomethyl ether (IC50 = 1.88 µM) on CYP2C19 was comparable to that of CBD, although the inhibitory potency of CBD-2′,6′-dimethyl ether (IC50 = 14.8 µM) was lower than that of CBD. Cannabidivarin, possessing a propyl side chain, showed slightly less potent inhibition (IC50 = 3.45 µM) as compared with CBD, whereas orcinol and resorcinol did not inhibit CYP2C19 activity at all. These results indicate that CBD caused potent CYP2C19 inhibition, in which one free phenolic hydroxyl group and the pentyl side chain of CBD may play important roles.

著者

Akiko MATSUI-SAKATA Hisakazu OHTANI Yasufumi SAWADA

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

Drug Metabolism and Pharmacokinetics (ISSN:13474367)

巻号頁・発行日

vol.20, no.5, pp.368-378, 2005 (Released:2005-11-01)

参考文献数

96

被引用文献数

138

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Objective: Among various adverse reactions of atypical antipsychotics, weight gain and impaired glucose tolerance are clinically significant. The aim of this study is to analyze quantitatively the contributions of various receptors to these antipsychotics-induced adverse reactions based on the receptor occupancy theory.    Methods: Two indices of antipsychotics-induced weight gain (the values estimated by a meta-analysis and the observed values in clinical trials) and the morbidity rate of type 2 diabetes mellitus during treatment with antipsychotics were taken from the literature. We calculated the estimated mean receptor occupancies of α1 adrenergic, α2 adrenergic, dopamine D2, histamine H1, muscarinic acetylcholine (mACh), serotonin 5-HT1A, 5-HT2A and 5-HT2C receptors by antipsychotics by using the pharmacokinetic parameters and receptor dissociation constants, and analyzed the correlation between the occupancies and the extent of adverse reactions as assessed using the aforementioned indices.    Results: There were statistically significant correlations between the estimated occupancies of H1 and mACh receptors and antipsychotics-induced weight gain estimated by meta-analysis (rs=0.81 and rs=0.83, respectively, p<0.01). There were also statistically significant correlations between these receptor occupancies and observed weight gain in clinical trials (rs=0.66 in each case, p<0.01). The morbidity rate of type 2 diabetes mellitus was highly correlated with H1, mACh, and 5-HT2C receptor occupancies (rs=0.90 in each case, p<0.05). However, H1 receptor occupancy was also highly correlated with mACh receptor occupancy among antipsychotics, so that only one of them may be critically associated with the adverse reactions. Considering that these adverse reactions have not been reported for drugs with mACh receptor antagonistic action, other than antipsychotics, the H1 receptor may contribute predominantly to the antipsychotics-induced weight gain and diabetes mellitus.    Discussion/Conclusion: Model analysis based on receptor occupancy indicates that H1 receptor blockade is the primary cause of antipsychotics-induced weight gain and diabetes mellitus.

著者

Satoshi YAMAORI Kyoko KOEDA Mika KUSHIHARA Yui HADA Ikuo YAMAMOTO Kazuhito WATANABE

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

Drug Metabolism and Pharmacokinetics (ISSN:13474367)

巻号頁・発行日

vol.27, no.3, pp.294-300, 2012 (Released:2012-06-25)

参考文献数

38

被引用文献数

95

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Inhibitory effects of Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), and cannabinol (CBN), the three major constituents in marijuana, and polycyclic aromatic hydrocarbons (PAHs) contained in marijuana smoke on catalytic activity of human cytochrome P450 (CYP) 2C9 were investigated. These phytocannabinoids concentration-dependently inhibited S-warfarin 7-hydroxylase and diclofenac 4′-hydroxylase activities of human liver microsomes (HLMs) and recombinant CYP2C9 (rCYP2C9). In contrast, none of the twelve PAHs including benz[a]anthracene and benzo[a]pyrene exerted substantial inhibition (IC50 > 10 µM). The inhibitory potentials of Δ9-THC (Ki = 0.937–1.50 µM) and CBN (Ki = 0.882–1.29 µM) were almost equivalent regardless of the enzyme sources used, whereas the inhibitory potency of CBD (Ki = 0.954–9.88 µM) varied depending on the enzyme sources and substrates used. Δ9-THC inhibited both S-warfarin 7-hydroxylase and diclofenac 4′-hydroxylase activities of HLMs and rCYP2C9 in a mixed manner. CBD and CBN competitively inhibited the activities of HLMs and rCYP2C9, with the only notable difference being that CBD and CBN exhibited mixed-type inhibitions against diclofenac 4′-hydroxylation and S-warfarin 7-hydroxylation, respectively, by rCYP2C9. None of Δ9-THC, CBD, and CBN exerted metabolism-dependent inhibition. These results indicated that the three major phytocannabinoids but not PAHs contained in marijuana smoke potently inhibited CYP2C9 activity and that these cannabinoids can be characterized as direct inhibitors for CYP2C9.

著者

川口 輝久 久保 正則 宮内 俊 秋山 仁 小富 正昭

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.9, no.5, pp.628-650, 1994 (Released:2007-03-29)

参考文献数

19

被引用文献数

2

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BOF-A2(3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl]-1-ethoxymethyl-5-fluorouracil)をラットに単回および反復経口投与後の主代謝産物である1-ethoxymethyl-5-fluorouracil(EM-FU),3-cyano-2,6-dihydroxy-pyridine(CNDP),5-fluorouracil(5-FU)の吸収,分布,代謝および排泄について検討した. 1.各代謝産物の血漿中濃度推移はSDおよびDonryu系雄性ラットで差は認められなかった. 2.投与量の増加にともなって各代謝産物のCmaxおよびAUCo.72比も増加したが,1000mg/kg投与群ではやや頭打ちになる傾向が認められた. 3.5-FUとCNDPの併用投与あるいはEM-FUとCNDPの併用投与の場合よりも,BOF-A2投与の場合が血漿中5-FU濃度は最も長く持続した. 4.絶食あるいは非絶食下に雄性ラットに単回経口投与後,EM-FUは非絶食下投与の方が,CNDPおよび5-FUは絶食下投与の方が高い血漿中濃度推移を示した. 5.雌雄ラットに単回経口投与後,EM-FUは雌が,5-FUは雄が高い血漿中濃度推移を示した. 6.担癌雄性ラットにおける血中5-FUは,正常ラットよりも低い濃度推移を示した.これらのEM-FU,5-FUの濃度推移の差は,主に,肝ミクロソームにおけるEM-FUから5-FUへの活性化酵素(EM-FU代謝酵素)活性の差により,CNDPの濃度推移の差は吸収の差によると考えられた. 7.雄性ラットに反復経口投与後7日目には,1日目に比べて,EM-FUが高い血漿中濃度推移を示し,5-FUが低い推移を示した. 8.雌雄ラットに単回経口投与後2~8時間に,EM-FU,CNDP,5-FUは消化管,腎臓などで血漿中よりも高い濃度を示したが,24時間までには速やかに減少した.また,雄性ラットでの反復投与において,各代謝産物ともに組織への蓄積性は認められなかった. 9.雄性ラットにシメチジンおよびシスプラチンをBOF-A2と同時投与した場合,BOF-A2単独投与群に比べて,EM-FUの血漿中濃度および尿中排泄率が増加し,5-FUの血漿中濃度および尿中排泄率は減少したことから,シメチジソおよびシスプラチンによるEM-FU代謝酵素活性の抑制が推察された. 10.雄性ラットに単回経口投与後48時間までに,EM-FUが6.8%,5-FUが17.9%,CNDPが58.4%尿中へ排泄された.糞中にはBOF-A2が6.6%検出された。また,胆汁中排泄率は各代謝産物ともにわずかであった. 11.雄性ラットに反復経口投与した場合,尿中へのEM-FUの排泄率は増加し,5-FUの排泄率は若干減少する傾向が認められた. 12.雄性ラットに3,10,30mg/kgの用量で1日1回14日間反復経口投与後,NADPH Cyto-chrome C reductase活性が用量依存的に減少し,また,30mg/kg投与では,DHUDase活性が増加した.

著者

Jahye KIM Hisakazu OHTANI Masayuki TSUJIMOTO Yasufumi SAWADA

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

Drug Metabolism and Pharmacokinetics (ISSN:13474367)

巻号頁・発行日

vol.24, no.2, pp.167-174, 2009 (Released:2009-05-10)

参考文献数

41

被引用文献数

12

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Concomitant administration of certain fluoroquinolone antimicrobials and nonsteroidal antiinflammatory agents (NSAIDs) induces serious convulsion in humans. There are differences in convulsive activity among fluoroquinolones and in the potentiation of fluoroquinolone-induced convulsion among NSAIDs, but a comprehensive, quantitative comparison has not been carried out. This study evaluates the inhibitory effects of twelve fluoroquinolones (ciprofloxacin, enoxacin, fleroxacin, gatifloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, pazufloxacin, prulifloxacin, sparfloxacin, and tosufloxacin) alone or in the presence of an NSAID (4-biphenylacetic acid, diclofenac sodium, loxoprofen, lornoxicam or zaltoprofen) on the GABAA receptor binding of [3H]muscimol in an in vitro study using mice synaptic plasma membrane. The rank order of inhibitory effects of the fluoroquinolones was prulifloxacin ≈ norfloxacin > ciprofloxacin ≥ enoxacin > gatifloxacin ≥ ofloxacin ≈ tosufloxacin ≈ lomefloxacin > levofloxacin ≥ sparfloxacin ≥ pazufloxacin ≈ fleroxacin. 4-Biphenylacetic acid most potently enhanced the inhibitory effects of the fluoroquinolones, while zaltoprofen, loxoprofen, lornoxicam and diclofenac had essentially no effect. The clinical risk of convulsion for each combination was estimated using a pharmacodynamic model based on receptor occupancy using the in vitro data set obtained and pharmacokinetic parameters in humans collected from the literature. The combinations of 4-biphenylacetic acid with prulifloxacin and enoxacin were concluded to be the most hazardous.

著者

渥美 亮 鈴木 亘 吉田 伸子 伯水 英夫

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.5, no.2, pp.209-216, 1990 (Released:2007-03-29)

参考文献数

13

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To examine the drug interaction between LC9018 and tegafur, the tegafur was administered to LC9018 treated or control mice and plasma concentrations of tegafur and its active metabolite, 5-fluorouracil (5-FU) were monitored.1. In 300μg LC9018/animal (intravenous, i.v.) treated group, the maximum plasma level(Cmax) of 5-FU and the area under the curve (AUC)decreased to 43% and 64% of control values, respectively. On the other hand, no change was observed in tegafur level, suggesting that LC9018 inhibited the conversion of tegafur to 5-FU at this dose.2. In 300μg LC9018/animal (intrapleural, i. pl.) treated group, 5-FU level decreased to 55% of the control at 30min after administration. But the influence on the metabolism of tegafur was smaller compared to the intravenous treatment of LC9018.3. In 180μg/animal (i.v.), 150μg/animal (i.pl.) and 300μg LC9018/animal (subcutanous, s.c.) treated groups, both tegafur and 5-FU level did not alter compared to the control.4. From above results, influence of LC9018 on the metabolism of tegafur depends on the dose and the administration route (i.v.> i.pl.> s.c.). It is considered that LC9018 slightly affects the metabolism of tegafur at clinical dose (200μg/animal i.pl.).

著者

Eriko SATO Ikuko YANO Masahiro SHIMOMURA Satohiro MASUDA Toshiya KATSURA Shin-ichi MATSUMOTO Teru OKITSU Yasuhiro IWANAGA Shinji UEMOTO Ken-ichi INUI

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

Drug Metabolism and Pharmacokinetics (ISSN:13474367)

巻号頁・発行日

vol.24, no.2, pp.175-179, 2009 (Released:2009-05-10)

参考文献数

20

被引用文献数

3

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We attempted a switch of mammalian target of rapamycin (mTOR) inhibitors from sirolimus to everolimus, a derivative of sirolimus and now on the market in Japan, in two pancreatic islet transplant patients. Both patients were administered tacrolimus with sirolimus or everolimus. They had been administered 5 or 9 mg sirolimus once a day and had maintained a trough concentration of about 15 ng/mL as measured by high performance liquid chromatography with ultraviolet detection. After the switch from sirolimus to everolimus, they were given 10 or 12 mg/day of everolimus twice a day to maintain a trough concentration of 12-15 ng/mL as measured by a fluorescence polarization immunoassay (FPIA) method. Afterward, the blood concentrations of everolimus and sirolimus after the conversion were measured by high performance liquid chromatography with mass spectrometry and everolimus concentrations were found to be 5-10 ng/mL. These data show that a larger dosage is needed for everolimus than sirolimus to maintain the same trough blood concentration. Data obtained by the FPIA for everolimus should be carefully evaluated after switching from sirolimus to everolimus because of the cross-reactivity of the antibody with sirolimus.

著者

嶋田 薫

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.16, no.supplement, pp.152-153, 2001-09-17 (Released:2007-03-29)

参考文献数

10

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The Caco-2 human-epithelial cell line has been widely used as a tissue-culture model for permeability measurements to predict human oral absorption in the drug discovery stage. In my presentation I will address some of the strategic applications of the Caco-2 model. Physicochemical properties affect the permeability. For example, permeability tends to be underestimated in hydrophilic compounds. For determining the permeability of poorly soluble drugs, some solubilizing reagents or bovine serum albumin can be used. The expression of some carrier-mediated transport systems has been confirmed on Caco-2 cell monolayers; therefore, we should pay attention to evaluating compounds that may be substrates of the transporters. The pH of the medium also affects the result of this assay. Transport studies with an apical pH value at 6.0 or 6.5 showed better prediction of in vivo drug absorption in human. For compounds that are substrates of P-glycoprotein (Pgp), the use of a Pgp inhibitor resulted in a better estimate of absorption in humans. The results suggest that compounds can be ranked according to how well they are absorbed; namely, those with Papp less than 1×10-6cm/s (poorly absorbed), between 1×10-6cm/s and 1×10-5cm/s (moderately absorbed), and greater than 1×10-5cm/s (well absorbed). The data of the Caco-2 assays are sometimes different, however, from those in different laboratories due to fluctuations in permeability resulting from passages and culture conditions, even when using the same clone. For high throughput screening, the permeability in 96-well Caco-2 assay demonstrates a good correlation with known human absorption for a variety of compounds. This is comparable to a 24-well system. Automation machines can be successfully applied for Caco-2 assays. Several in silicostudies for the prediction of Caco-2 permeability have also been conducted. A database system to which scientists easily access should be developed in collaboration with information-technologyg roups.

著者

Keiko MAEKAWA Masaya ITODA Kimie SAI Yoshiro SAITO Nahoko KANIWA Kuniaki SHIRAO Tetsuya HAMAGUCHI Hideo KUNITOH Noboru YAMAMOTO Tomohide TAMURA Hironobu MINAMI Kaoru KUBOTA Atsushi OHTSU Teruhiko YOSHIDA Nagahiro SAIJO Naoyuki KAMATANI Shogo OZAWA Jun-ichi SAWADA

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

Drug Metabolism and Pharmacokinetics (ISSN:13474367)

巻号頁・発行日

vol.21, no.2, pp.109-121, 2006 (Released:2006-05-10)

参考文献数

35

被引用文献数

35

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The ATP-binding cassette transporter, ABCG2, which is expressed at high levels in the intestine and liver, functions as an efflux transporter for many drugs, including clinically used anticancer agents such as topotecan and the active metabolite of irinotecan (SN-38). In this study, to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of ABCG2, we have comprehensively searched for genetic variations in the putative promoter region, all the exons, and their flanking introns of ABCG2 from 177 Japanese cancer patients treated with irinotecan. Forty-three genetic variations, including 11 novel ones, were found: 5 in the 5′-flanking region, 13 in the coding exons, and 25 in the introns. In addition to 9 previously reported nonsynonymous single nucleotide polymorphisms (SNPs), 2 novel nonsynonymous SNPs, 38C>T (Ser13Leu) and 1060G>A (Gly354Arg), were found with minor allele frequencies of 0.3%. Based on the LD profiles between the SNPs and the estimated past recombination events, the region analyzed was divided into three blocks (Block -1, 1, and 2), each of which spans at least 0.2 kb, 46 kb, and 13 kb and contains 2, 24, and 17 variations, respectively. The two, eight, and five common haplotypes detected in 10 or more patients accounted for most (>90%) of the haplotypes inferred in Block -1, Block 1, and Block 2, respectively. The SNP and haplotype distributions in Japanese were different from those reported previously in Caucasians. This study provides fundamental information for the pharmacogenetic studies investigating the relationship between the genetic variations in ABCG2 and pharmacokinetic/pharmacodynamic parameters.

著者

山田 安彦 櫻井 和子 中村 幸一 澤田 康文 伊賀 立二

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.8, no.3, pp.283-293, 1993-06-30 (Released:2007-03-29)

参考文献数

46

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It is well known that change in drug distribution occur in association with hepatic disease. The prediction of the variation in the volume of distribution of drugs at steady-state (Vdss) in hepatic disease is very useful for the planning of drug dosage regimens. In the present study, we tried to develop methodology for estimating Vdss in hepatic disease based on physiological pharmacokinetics. The following two methods were utilized to predict Vdss in hepatic disease (hepatic cirrhosis and hapatitis). Method 1 : Vdss in hepatic disease was predicted assuming that Vdss in hepatic disease is not different from that in the normal condition. Method 2 : it is assumed that hepatic disease could not lead to alterations in the tissue binding but in the plasma binding, Vdss in hepatic disease was calculated according to the mass balance equation (Vdss=7.2+7.8·fP+27·fp/fT ; where fP and fT are plasma and tissue unbound fraction, respectively) by using the data of Vdss and fp in normal condition and that in hepatic disease. In hapatic cirrhosis, a significant correlation between the observed and predicted values according to Method 1 was obtained with a slope of regression line of 0.79 (p<0.001). On the other hand, a significant linear correlation between the observed and predicted values according to Method 2 was obtained with a slope of 1.03 (p<0.001). Furthermore, a significant difference in percent errors between the two methods was observed (p<0.05). In hepatitis, same resuls were also obtained. In conclusion, it is suggested that the extent of intrinsic tissue binding of various drugs is little altered in hepatic disease. The prediction of the apparent volume of distribution in hepatic disease according to Method 2 was successful for most drugs studied and very useful for clinical use.

著者

Xiao-cong ZUO Ya-nan ZHOU Bi-kui ZHANG Guo-ping YANG Ze-neng CHENG Hong YUAN Dong-sheng OUYANG Shi-kun LIU Jeffrey S. BARRETT Pei-jiong LI Zhi LIU Hong-yi TAN Ren GUO Ling-yun ZHOU Yue-liang XIE Zuo-jun LI Jing LI Chun-jiang WANG Jiang-lin WANG

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

Drug Metabolism and Pharmacokinetics (ISSN:13474367)

巻号頁・発行日

vol.28, no.5, pp.398-405, 2013 (Released:2013-10-25)

参考文献数

51

被引用文献数

18

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The objective of this study was to evaluate the effect of the CYP3A5*3 allele on the pharmacokinetics of tacrolimus and amlodipine, and drug-drug interactions between them in healthy subjects. Pharmacokinetic drug interactions between tacrolimus and amlodipine were evaluated in a randomized, 3-period, 6-sequence crossover study in healthy Chinese volunteers according to CYP3A5 genotype. A single-dose and multiple-dose study were designed. A 96-h pharmacokinetic study followed either tacrolimus or amlodipine dose, and the washout periods between the study phases were 14 days. In the single-dose study, apparent oral clearance (CL/F) of tacrolimus (5 mg) in CYP3A5 expressers was 3.8-fold (p = 0.008) higher than that in CYP3A5 non-expressers. Amlodipine decreased mean tacrolimus CL/F in CYP3A5 expressers by 2.2-fold (p = 0.005), while it had no effect on that in CYP3A5 non-expressers. The CL/F of amlodipine in CYP3A5 non-expressers was 2.0-fold (p = 0.001) higher than that in CYP3A5 expressers. Tacrolimus increased mean amlodipine CL/F in CYP3A5 expressers by 1.4-fold (p = 0.016) while it had no effect on that in CYP3A5 non-expressers. Tacrolimus slightly reduced the AUC0–∞ of amlodipine in both CYP3A5 expressers and non-expressers. Dose adjustment of tacrolimus should be considered according to CYP3A5*3 genetic polymorphism when tacrolimus is coadministered with amlodipine.

著者

Ger J. van der VUSSE

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

Drug Metabolism and Pharmacokinetics (ISSN:13474367)

巻号頁・発行日

vol.24, no.4, pp.300-307, 2009 (Released:2009-09-10)

参考文献数

62

被引用文献数

314

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Fatty acids play critical roles in mammalian energy metabolism. Moreover, they are important substrates for the synthesis of membrane phospholipids and biologically active compounds like eicosanoids and leukotrienes. Because of their low solubility in aqueous solutions such as blood plasma and interstitial fluid, fatty acids are in need of binding proteins to increase their concentration in vascular and interstitial compartments. Albumin acts as main fatty acid binding protein in extracellular fluids. Plasma albumin possesses about 7 binding sites for fatty acids with moderate to high affinity, enhancing the concentration of fatty acids by a several orders of magnitude. Despite the high affinity of albumin for fatty acids, uptake of fatty acids by parenchymal cells such as skeletal and cardiac myocytes seems not to be hampered by albumin. In contrast, experimental findings suggest that albumin may facilitate the uptake of fatty acids by organs in need of these substrates. In the present overview the following issues will be briefly discussed: (i) transport and storage of fatty acids in the mammalian body, (ii) biosynthesis of albumin in the liver, (iii) localization and concentration of albumin in body fluids, (iv) interactions between albumin and fatty acids, (v) albumin structure and fatty acid binding sites, (vi) uptake of fatty acids by organs and roles for plasma albumin and (vii) lessons from patients and experimental animals lacking plasma albumin.

著者

Li WANG Douglas H. SWEET

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

Drug Metabolism and Pharmacokinetics (ISSN:13474367)

巻号頁・発行日

vol.28, no.3, pp.220-228, 2013 (Released:2013-06-25)

参考文献数

44

被引用文献数

26

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When herbal products are used in combination therapy with drugs, alterations in pharmacokinetics, pharmacodynamics, and toxicity can result. Many active components of herbal products are organic anions, and human organic anion transporter 1 (hOAT1, SLC22A6), hOAT3 (SLC22A8), and hOAT4 (SLC22A11) have been identified as potential sites of drug-drug interactions. Therefore, we assessed the effects of lithospermic acid (LSA), rosmarinic acid (RMA), salvianolic acid A (SAA), salvianolic acid B (SAB), and tanshinol (TSL), components of the herbal medicine Danshen, on the function of these transporters. Kinetic analysis demonstrated a competitive mechanism of inhibition for all five. Ki values (µM) were estimated as 20.8 ± 2.1 (LSA), 0.35 ± 0.06 (RMA), 5.6 ± 0.3 (SAA), 22.2 ± 1.9 (SAB), and 40.4 ± 12.9 (TSL) on hOAT1 and as 0.59 ± 0.26 (LSA), 0.55 ± 0.25 (RMA), 0.16 ± 0.03 (SAA), 19.8 ± 8.4 (SAB), and 8.6 ± 3.3 (TSL) on hOAT3. No significant inhibition of hOAT4 activity by TSL was observed. Using published human pharmacokinetic values, unbound Cmax/Ki ratios were calculated as an indicator of in vivo drug-drug interaction potential. Analysis indicated a strong interaction potential for RMA and TSL on both hOAT1 and hOAT3 and for LSA on hOAT3. Thus, herb-drug interactions may occur in vivo in situations of co-administration of Danshen and clinical therapeutics known to be hOAT1/hOAT3 substrates.

著者

松本 宜明 清水 万紀子 福岡 正道

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.15, no.5, pp.452-460, 2000 (Released:2007-03-29)

参考文献数

42

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Recently, an increasing number of pharmaceutical scientists and clinical pharmacists have begun to focus on pharmacodynamics, which relates the time course of drug concentration to the time course of pharmacological effects. An integration knowledge of pharmacokinetics and pharmacodynamics is essential for the development of rational pharmacotherapeutics because pharmacodynamics and pharmacokinetics are able to determines the drug concentration required to produce the desired therapeutic effect and the drug dose regimen required to achieve the targeted drug concentration, respectively, by using various models. The general principles of the drug effect model are based on the reversible direct and indirect models. In this review, various models in terms of the time course of drug effects are presented and discussed.

著者

杉林 堅次

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.2, no.1, pp.71-80, 1987 (Released:2007-03-29)

参考文献数

37

被引用文献数

1

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Transdermal absorption of drugs, i.e. nitroglycerin and scoporamine, from marketed transdermal therapeutic systems (TTS) has been evaluated mainly according to T. Higuchi's theory. This theory, at first, was reviewed from the thermodynamic point of view. Much attention is paid to the enhanced transdermal absorption to expand the utility of TTS to many drugs and it becomes realistic by use of prodrugs as esters of viderabine, an antivirus drug, by the application of penetration-enhancers such as Azone, and/or by appearance of iontophoresis. Secondly, such enhancing systems were summarized theoretically and the differences between them and Higuchi's theory on the absorption rates were discussed. The route for transdermal absorption and its kinetic model might be modified in such enhancing systems, since the systems affect the skin barrier function. Reasonable absorption routes and skin model were discussed, thirdly. These three considerations could be useful for the development and evaluation of new TTS.

著者

Tatsuya YAGI Takafumi NAITO Yasuaki MINO Kazuo UMEMURA Junichi KAWAKAMI

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

Drug Metabolism and Pharmacokinetics (ISSN:13474367)

巻号頁・発行日

vol.27, no.2, pp.248-254, 2012 (Released:2012-04-25)

参考文献数

27

被引用文献数

13

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The aim of this open-label, randomized, and 3-period crossover study was to evaluate the influences of concomitant antacid administration on the plasma disposition, intestinal absorption, and urinary excretion of gabapentin in humans. Gabapentin (200 mg) was orally administered alone, with 1 g magnesium oxide (MgO), or with 20 mg omeprazole to 13 healthy adult subjects. Oral bioavailability (BA) of gabapentin was estimated by 24-h urine collection. The Cmax, Tmax and AUC0–∞ of gabapentin + MgO were significantly lower than that of gabapentin alone (by 33%, 36% and 43%, respectively) and gabapentin + omeprazole (by 29%, 46% and 40%, respectively). In contrast, no significant differences were observed in the plasma disposition parameters of gabapentin between the treatments with and without omeprazole. The gabapentin BA in the MgO treatment was significantly lower, by 32% and 39%, compared to the gabapentin alone and with omeprazole treatment, respectively. There was no significant difference in the gabapentin BA between the gabapentin alone and with omeprazole treatment. Concomitant MgO and omeprazole did not affect the renal clearance of gabapentin. In conclusion, concomitant MgO decreased the gabapentin exposure through the reduction of intestinal absorption extent and rate. This reduction may be independent of the suppression of gastrointestinal acidification caused by antacids.