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Ichiro Ieiri,
Shyohei Tsunemitsu,
Kazuya Maeda,
Yukie Ando,
Noritomo Izumi,
Miyuki Kimura,
Naoe Yamane,
Tsuyoshi Okuzono,
Mariko Morishita,
Naoki Kotani,
Eri Kanda,
Mariko Deguchi,
Kyoko Matsuguma,
Shunji Matsuki, Takeshi Hirota,
Shin Irie,
Hiroyuki Kusuhara,
Yuichi Sugiyama
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ABSTRACT: We investigated the mechanisms of ritonavir-mediated enhancement effect on the pharmacokinetics of saquinavir using in vivo probes for CYP3A4 (midazolam), p-glycoprotein (fexofenadine), and OATP1B1 (pravastatin) following oral micro/small dosing. A cocktail of the drugs (2 mg of saquinavir, 100 µg of each probe) was administered to eight healthy volunteers (phase 1), and then coadministered with 20 mg (phase 2) and 100 mg (phase 3) of ritonavir. Plasma concentrations of the drugs were measured by validated LC-MS/MS methods. The mean plasma AUC(0-24) (pg hour/mL) of saquinavir at phases 1, 2, and 3 was 101, 2 540, and 23 900 (P < .01), respectively. The relative area under the plasma concentration-time curve (AUC)(0-24) ratios of midazolam and fexofenadine at phases 1, 2, and 3 were 1:5.9:14.7 (P < .01), and 1:1.4:2.2 (P < .01-.05), respectively. In contrast, there was no difference in the pharmacokinetics of pravastatin. Inhibition of intestinal and hepatic CYP3A-mediated metabolism, and intestinal p-glycoprotein-mediated efflux of saquinavir, but not OATP1B1, is involved in the enhancement mechanism. Micro/small dosing is useful for examining the mechanism of drug interactions without safety concern.
The Journal of Clinical Pharmacology 02/2013; · 2.91 Impact Factor
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ABSTRACT: Human cytochrome P450 (CYP) is a superfamily of hemoproteins which oxidize a number of endogenous compounds and xenobiotics. The human CYP2C subfamily consists of four members; CYP2C8, CYP2C9, CYP2C18 and CYP2C19. CYP2C9 and CYP2C19 are important drug metabolizing enzymes and together metabolize approximately 20% of therapeutically used drugs. Forty two allelic variants for CYP2C9 and 34 for CYP2C19 have been reported. The frequencies of these variants show marked inter-ethnic variation. The functional consequences of genetic polymorphisms have been examined, and many studies have shown the clinical importance of these polymorphisms. Current evidence suggests that taking the genetically determined metabolic capacity of CYP2C9 and CYP2C19 into account has the potential to improve individual risk/benefit relationships. However, more prospective studies with clinical endpoints are needed before the paradigm of 'personalized medicine' based on the variants can be established. This review summarizes the currently available important information on this topic.
Drug Metabolism and Pharmacokinetics 11/2012; · 2.32 Impact Factor
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Ichiro Ieiri,
Masato Fukae,
Kazuya Maeda,
Yukie Ando,
Miyuki Kimura, Takeshi Hirota,
Takeshi Nakamura,
Kazuhide Iwasaki,
Shunji Matsuki,
Kyoko Matsuguma,
Eri Kanda,
Mariko Deguchi,
Shin Irie,
Yuichi Sugiyama
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ABSTRACT: Objectives: To test whether the multiple phenotype and genotype relationships established using therapeutic dose, can be reproduced following oral microdosing using substrates of CYP2C9 (warfarin and glibenclamide), CYP2C19 (lansoprazole), CYP2D6 (dextromethorphan), and OATPs (glibenclamide). Methods: A cocktail of test drugs was administered orally under the microdose in liquid or capsule form, and then a therapeutic dose of dextromethorphan was administered to 17 healthy subjects whose genotypes for CYPs and OATPs had been prescreened. Concentrations of the drugs and their metabolites were measured by LC-MS/MS. Results: The AUC and t1/2 of glibenclamide following the microdosing tended to be higher and longer, respectively, in CYP2C9*1/*3 than CYP2C9*1/*1 subjects. In contrast, there were no significant differences in any of the pharmacokinetic parameters for warfarin between the two genotypes. For CYP2D6 following the therapeutic dose, there was good concordance between genotype and phenotype; however, such relationships disappeared after microdosing. For CYP2C19 following the microdosing, there were significant differences between EMs and PMs in the pharmacokinetic parameters of lansoprazole. The relative AUC0-12 ratio of lansoprazole in EMs and PMs was 1:3.3 - 4.3. Among test drugs, phenotypic measurements of lansoprazole accorded well with the CYP2C19 genotype at the microdose as well as therapeutic dose. Conclusions: The present study suggests that 1) the sampling strategy should be optimized according to pharmacokinetic profiles of the test drugs following oral microdosing, and 2) microdosing can be applied to the pharmacogenomic study of CYP-specific drugs.
International journal of clinical pharmacology and therapeutics 08/2012; 50(10):689-700. · 1.18 Impact Factor
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Takeshi Hirota,
Yuko Date,
Yu Nishibatake,
Hiroshi Takane,
Yasushi Fukuoka,
Yuuji Taniguchi,
Naoto Burioka,
Eiji Shimizu,
Hiroshige Nakamura,
Kenji Otsubo,
Ichiro Ieiri
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ABSTRACT: Dihydropyrimidine dehydrogenase (DPD) is important to the antitumor effect of 5-fluorouracil (5-FU). DPD gene (DPYD) expression in tumors is correlated with sensitivity to 5-FU. Because the 5-FU accumulated in cancer cells is also rapidly converted into inactivated metabolites through catabolic pathways mediated by DPD, high DPD activity in cancer cells is an important determinant of the response to 5-FU. DPD activity is highly variable and reduced activity causes a high risk of 5-FU toxicity. Genetic variation in DPYD has been proposed as the main factor responsible for the variation in DPD activity. However, only a small proportion of the activity of DPD can be explained by DPYD mutations. In this study, we found that DPYD is a target of the following microRNAs (miRNA): miR-27a, miR-27b, miR-134, and miR-582-5p. In luciferase assays with HepG2 cells, the overexpression of these miRNAs was associated with significantly decreased reporter activity in a plasmid containing the 3'-UTR of DYPD mRNA. The level of DPD protein in MIAPaca-2 cells was also significantly decreased by the overexpression of these four miRNAs. The results suggest that miR-27a, miR-27b, miR-134, and miR-582-5p post-transcriptionally regulate DPD protein expression. The levels of miRNAs in normal lung tissue and lung tumors were compared; miR-27b and miR-134 levels were significantly lower in the tumors than normal tissue (3.64 ± 4.02 versus 9.75 ± 6.58 and 0.64 ± 0.75 versus 1.48 ± 1.39). DPD protein levels were significantly higher in the tumors. Thus, the decreased expression of miR-27b would be responsible for the high levels of DPD protein. This study is the first to show that miRNAs regulate the DPD protein, and provides new insight into 5-FU-based chemotherapy.
Lung cancer (Amsterdam, Netherlands) 02/2012; 77(1):16-23. · 3.14 Impact Factor
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Ichiro Ieiri,
Yohei Doi,
Kazuya Maeda,
Tomohiro Sasaki,
Miyuki Kimura, Takeshi Hirota,
Takeshi Chiyoda,
Mayuko Miyagawa,
Shin Irie,
Kazuhide Iwasaki,
Yuichi Sugiyama
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ABSTRACT: The authors evaluated the contribution of the SLCO2B1 polymorphism to the pharmacokinetics of celiprolol at a microdose (MD) and therapeutic dose (TD) and compared pharmacokinetic proportionality between the 2 dose forms in 30 SLCO2B1 genotype-matched healthy volunteers. Three drugs (celiprolol, fexofenadine, and atenolol) were orally administered as a cassette dosing following the MD (totally 97.5 µg) and then a TD (100 mg) of celiprolol, with and without grapefruit juice. The mean AUC(0-24) of celiprolol was lower in SLCO2B1*3/*3 individuals (775 ng·h/mL) than in *1/*3 (1097 ng·h/mL) and *1/*1 (1547 ng·h/mL) individuals following the TD, and this was confirmed in population pharmacokinetic analysis with statistical significances; however, SLCO2B1 genotype-dependent differences disappeared following the MD. Dose-normalized AUC of celiprolol at the MD was much lower than that at the TD, explained by the saturation of the efflux transporter. Thus, the effect of SLCO2B1 polymorphism on the AUC of celiprolol clearly observed only at the TD may be due to the saturation of the efflux transport systems.
The Journal of Clinical Pharmacology 05/2011; 52(7):1078-89. · 2.91 Impact Factor
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ABSTRACT: Organic cation transporters (OCTs) mediate the transport of organic cations and some drugs (e.g., metformin and cimetidine). OCT1, OCT2, and OCT3 are located in the imprinting cluster of the insulin-like growth factor 2 receptor. It has been reported that OCT1 and OCT3 show a biallelic expression, whereas OCT2 undergoes maternal imprinting in the human placenta; however, a loss of the imprinting of OCT2 has recently been reported in some placental samples. This study investigated whether epigenetic mechanisms are involved in interindividual differences in the placental expression of OCT2. Because OCT2 mRNA levels were higher in biallelic samples than that in monoallelic samples, we compared the DNA methylation and chromatin modifications in the promoter regions. There was no remarkable difference in DNA methylation between the mono allelic samples and biallelic samples. In contrast, histone H3 acetylation (H3Ac) was increased in the biallelic samples. A significant negative correlation was observed between the trimethylation of lysine-9 on histone H3 (H3K9me3) and the OCT2 mRNA levels. Our results suggest that H3Ac plays a role in the allelic expression of OCT2. In addition, H3K9me3 in the OCT2 promoter may explain the interindividual differences in placental OCT2 mRNA levels.
Journal of Pharmaceutical Sciences 04/2011; 100(9):3875-83. · 3.06 Impact Factor
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ABSTRACT: The present study was undertaken to identify genetic polymorphisms of multidrug resistance-associated protein 3 (MRP3, gene name ABCC3), an ATP-binding cassette transporter that mediates the transport of substrates across the basolateral membrane into the blood, and to investigate their effects on ABCC3 expression and MRP3 function. We identified genetic polymorphisms of ABCC3 and evaluated the effects by (1) a luciferase reporter gene assay, (2) measuring mRNA levels, and (3) a human pharmacogenomics study with 4-methylumbelliferone glucuronide (4-MUG). Overall, 61 genetic variants were identified in three ethnic populations; of these variants 17 were novel (7 were non-synonymous: 61Arg>Cys, 132Gln>Stop, 221Trp>Stop, 270His>Gln, 548Leu>Gln, 600Lys>Arg, and 1324Arg>His). However, these mutations occurred at very low frequencies (max. 4.7%). The observed allele frequencies showed considerable inter-ethnic differences. The reporter gene assay indicated a significant reduction of transcriptional activity with the -1767G>A allele compared to the wild-type allele; however, a decreased expression of ABCC3 mRNA was not detected in human liver samples. A human pharmacokinetic study showed that the ABCC3 genotype in the promoter region was not associated with changes in the pharmacokinetics of 4-MUG, a substrate of MRP3. This is the first study to assess the effects of ABCC3 polymorphisms on human pharmacokinetics; however, further investigations are needed to complete the picture.
Drug Metabolism and Pharmacokinetics 04/2011; 26(4):374-86. · 2.32 Impact Factor
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ABSTRACT: Linezolid is an antimicrobial agent to treat infections by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). While effective, linezolid treatment frequently is associated with hematological side effects, especially thrombocytopenia. However, little is known about the mechanism of this side effect and the exposure-response relationship. The present population pharmacokinetic/pharmacodynamic (PPK/PD) study was undertaken to elucidate the factors that determine linezolid levels, the relationship between exposure to linezolid and a decrease in platelet counts, and appropriate dosage adjustments based on exposure levels. In total, 50 patients (135 plasma samples) were used for the PPK analysis. The PPK analysis revealed that renal function and severe liver cirrhosis (Child Pugh grade C) significantly affect the pharmacokinetics of linezolid according to the equation clearance (liter/h)=2.85×(creatinine clearance/60.9)0.618×0.472CIR (CIR indicates cirrhosis status; 0 for noncirrhosis, 1 for cirrhosis patients). Using 603 platelet counts from 45 patients, a PPK/PD analysis with a semimechanistic pharmacodynamic model described the relationship between linezolid exposure and platelet counts quantitatively, and the newly constructed model was validated using external data (776 platelet counts from 60 patients). Simulation indicated considerable risks in patients with insufficient renal function (creatinine clearance, ≤30 ml/min) or severe liver cirrhosis. For these patients, a reduced dosage (600 mg/day) would be recommended for sufficient efficacy (area under the concentration-time curve over 24 h in the steady state divided by the MIC, >100) and safety.
Antimicrobial Agents and Chemotherapy 02/2011; 55(5):1867-73. · 4.84 Impact Factor
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Daisuke Kanda,
Hitoshi Takagi,
Yasutsugu Kawahara,
Yutaka Yata,
Tomofumi Takakusagi,
Takeshi Hatanaka,
Teruo Yoshinaga,
Keigo Iesaki,
Kenji Kashiwabara,
Tsugio Higuchi,
Masatomo Mori, Takeshi Hirota,
Shun Higuchi,
Ichiro Ieiri
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ABSTRACT: The Dubin-Johnson syndrome (DJS) is an inherited liver disorder characterized by conjugated hyperbilirubinemia and caused by ABCC2 gene mutations resulting in deficiency of multidrug resistance associated-protein 2 (MRP2) function. A 76-year-old woman with serious jaundice was referred to our hospital. She was clinically diagnosed with DJS with hepatic congestion, due to constrictive pericarditis. We analyzed all exons and exon-intron junctions of the ABCC2 gene by DNA sequencing and identified a new large-scale deletion, 1008 bp, including the whole exon 7, as homozygosity. Some mutations in the ABCC2 gene associated with splicing errors have been reported in intronic regions; however, this is a new type of large-scale deletion detectable in the genomic DNA sequence. Severe hyperbilirubinemia is rare in patients with constrictive pericarditis and this case suggests that MRP2 may play a crucial role in compensating for the serum bilirubin in congestive hepatopathy.
Drug Metabolism and Pharmacokinetics 01/2009; 24(5):464-8. · 2.32 Impact Factor
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ABSTRACT: Drug metabolizing enzymes and transporters are increasingly recognized as key determinants of the inter-individual variability in pharmacokinetic (PK) and pharmacodynamic (PD) outcomes of clinically important drugs. To date, most studies investigating this variability have focused on polymorphisms (e.g. SNPs) in the genes encoding metabolic enzymes and transporters; however, it has recently been reported that the expression of some of these genes is under the control of epigenetic mechanisms. The most common epigenetic mechanism of mammalian genome regulation is DNA methylation, which does not change the genetic code but affects gene expression. Owing to its maintenance of the genomic sequence, DNA methylation is expected to offer an explanation for the controversial phenotypes of certain genetic polymorphisms. It has been recognized that DNA methylation plays a role in the transcriptional regulation of some PK/PD genes. In this review, we describe the impact of various epigenetic mechanisms, especially DNA methylation, on the expression (or activity) of drug metabolizing enzymes and transporter genes.
Current Drug Metabolism 02/2008; 9(1):34-8. · 5.11 Impact Factor
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ABSTRACT: The impact of SLCO1B1 polymorphism on the pharmacokinetics of olmesartan and on the pharmacokinetic interaction between pravastatin and olmesartan was investigated. On day 1, ten healthy volunteers took an oral dose (10 mg) of pravastatin. After a 3-day washout period, each subject received olmesartan medoxomil (10 mg) for 3 days. On day 8, they received olmesartan medoxomil (10 mg) and pravastatin (10 mg) concurrently, and pharmacokinetic profiles were compared with those in each single-dose phase with regard to the SLCO1B1 genotypes (*1b/*1b, *1b/*15, and *15/*15). In the single-dose phase, the mean C (max) and AUC(0-24) of olmesartan tended to be higher in *15/*15 subjects than in *1b/*1b subjects, while the mean CL( t )/F (+/-SD) in *15/*15 subjects was significantly lower than that in *1b/*1b subjects. No statistically significant differences were observed in any pharmacokinetic parameters between single-dose and co-administration phases for both pravastatin and RMS-416. These results suggest that OATP1B1 plays a role in the pharmacokinetics of olmesartan, and the co-administration of olmesartan does not affect the pharmacokinetics of pravastatin or its metabolite, RMS-416, although larger scale clinical studies are needed to confirm these observations due to the small sample size in the present study.
Journal of Human Genetics 01/2008; 53(10):899-904. · 2.57 Impact Factor
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ABSTRACT: There has been increasing appreciation of the role of drug transporters in pharmacokinetic and pharmacodynamic consequences in pharmacotherapy. The clinical relevance of drug transporters depends on the localisation in human tissues (i.e., vectorial movement), the therapeutic index of the substrates and inherent interindividual variability. With regard to variability, polymorphisms of drug transporter genes have recently been reported to be associated with alterations in the pharmacokinetics and pharmacodynamics of clinically useful drugs. A growing number of preclinical and clinical studies have demonstrated that the application of genetic information may be useful in individualised pharmacotherapy for numerous diseases. However, the reported effects of variants in certain drug transporter genes have been inconsistent and, in some cases, conflicting among studies. Furthermore, the incidence of almost all known variants in transporter genes tends to be racially dependent. These observations suggest the necessity of considering interethnic variability before extrapolating pharmacokinetic data obtained in one ethic group to another, especially in the early phase of drug development. This review focuses on the impact of genetic variations in the function of drug transporters (ABC, organic anion and cation transporters) and the implications of these variations for pharmacotherapy from pharmacokinetic and pharmacodynamic viewpoints.
Expert Opinion on Drug Metabolism & Toxicology 11/2006; 2(5):651-74. · 3.12 Impact Factor
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Daisuke Kobayashi,
Ichiro Ieiri, Takeshi Hirota,
Hiroshi Takane,
Shinji Maegawa,
Junzo Kigawa,
Hiroshi Suzuki,
Eiji Nanba,
Mitsuo Oshimura,
Naoki Terakawa,
Kenji Otsubo,
Kazunori Mine,
Yuichi Sugiyama
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ABSTRACT: The aim of the present study was to assess the contribution of polymorphisms in the breast cancer resistance protein/ATP-binding cassette transporter G2 (BCRP/ABCG2) gene to the placental expression from a new perspective, allelic imbalance. Polymorphisms were screened by polymerase chain reaction (PCR)-single-strand conformation polymorphism analysis followed by sequencing with DNA extracted from 100 placentas. To examine whether polymorphisms of the BCRP gene correlate with the placental BCRP expression, we determined mRNA and protein levels by quantitative real-time PCR and Western blotting, respectively. In placentas, G34A (Val(12)Met) and C421A (Gln(141)Lys) were frequently observed (18-36%), but C376T, which creates a stop codon (Gln(126) stop codon), was found with an allelic frequency of 1%. The mean of the BCRP protein level was significantly lower (p < 0.05) in homozygotes for the A421 allele than in those for the C421 allele, and heterozygotes had an intermediate value. To evaluate whether the C421A polymorphism acts as a cis-element in BCRP transcription, allelic imbalance was determined using informative lymphoblasts and 56 samples of placental cDNA. In most of the placental samples we tested, the difference in expression levels between the two alleles was small, and only two samples indicated a monoallelic expression (i.e., preferential expression of one allele). These results suggest that 1) the predominant allelic expression pattern of BCRP in placental samples is biallelic, and 2) the mutation C421A is not a genetic variant acting in cis, but is considered to influence the translation efficiency.
Drug Metabolism and Disposition 01/2005; 33(1):94-101. · 3.73 Impact Factor
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Takeshi Hirota,
Ichiro Ieiri,
Hiroshi Takane,
Shinji Maegawa,
Masakiyo Hosokawa,
Kaoru Kobayashi,
Kan Chiba,
Eiji Nanba,
Mitsuo Oshimura,
Tetsuo Sato,
Shun Higuchi,
Kenji Otsubo
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ABSTRACT: The human cytochrome P450 3A4 (CYP3A4) plays a dominant role in the metabolism of numerous clinically useful drugs. Alterations in the activity or expression of this enzyme may account for a major part of the variation in drug responsiveness and toxicity. However, it is generally accepted that most of the known single nucleotide polymorphisms in the coding and 5'-flanking regions are not the main determinants for the large inter-individual variability of CYP3A4 expression and activity. We show that the allelic variation is critically involved in determining the individual total hepatic CYP3A4 mRNA level and metabolic capability. There exists a definite correlation between the total CYP3A4 mRNA level and allelic expression ratio, the relative transcript level ratio derived from the two alleles. Individuals with a low expression ratio, exhibiting a large difference of transcript level between the two alleles, revealed extremely low levels of total hepatic CYP3A4 mRNA, and thus low metabolic capability as assessed by testosterone 6beta-hydroxylation. These results present a new insight into the individualized CYP3A4-dependent pharmacotherapy and the importance of expression imbalance to human phenotypic diversity.
Human Molecular Genetics 01/2005; 13(23):2959-69. · 7.64 Impact Factor
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ABSTRACT: Recently, a number of nucleotide variants have been described in the multidrug resistance 1 (MDR1/ABCB1) gene; however, most studies have focused on the coding region. In the present study, we identified promoter variants of the MDR1 gene and evaluated their phenotypic consequences using a reporter gene assay and the real-time polymerase chain reaction method. Ten allelic variants were detected in the promoter region (approximately 2 kilobases), seven of which were newly identified. Certain mutations occurred simultaneously, and a total of 10 haplotypes were observed. These promoter polymorphisms were found more frequently in Japanese than Caucasians. Some haplotypes were associated with changes in luciferase activity and placental and hepatic mRNA levels. We also determined DNA methylation status in the proximal promoter region of the MDR1 gene. The promoter region around potential binding sites for transcription factors was found to be hypomethylated and thus likely to be independent of the gene expression. Nucleotide and/or haplotype variants not only in the coding region but also in the promoter region of the MDR1 gene may be important for interindividual differences of P-glycoprotein expression.
Journal of Pharmacology and Experimental Therapeutics 01/2005; 311(3):1179-87. · 3.83 Impact Factor
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Yohei Nishizato,
Ichiro Ieiri,
Hiroshi Suzuki,
Miyuki Kimura,
Kiyoshi Kawabata, Takeshi Hirota,
Hiroshi Takane,
Shin Irie,
Hiroyuki Kusuhara,
Yoko Urasaki,
Akinori Urae,
Shun Higuchi,
Kenji Otsubo,
Yuichi Sugiyama
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ABSTRACT: Our objective was to quantitate the contribution of the genetic polymorphisms of the genes for 2 human organic anion transporters-organic anion transporting polypeptide C (OATP-C) and organic anion transporter 3 (OAT3)-to the pharmacokinetics of pravastatin.
Genetic polymorphisms were screened by polymerase chain reaction-single-strand conformation polymorphism analysis, after sequencing with deoxyribonucleic acid obtained from 120 healthy volunteers. To examine whether polymorphisms in these 2 genes of interest alter transport activity, we conducted a clinical study (n = 23) with pravastatin as a selective probe drug.
Among 120 healthy individuals, 5 nonsynonymous variants and 1 nonsynonymous variant were observed in the OATP-C and OAT3 genes, respectively. The polymorphisms in the OAT3 gene did not appear to be associated with changes in renal and tubular secretory clearance. In contrast, the OATP-C variants were associated with differences in the disposition kinetics of pravastatin. Subjects with the OATP-C*15 allele (Asp130Ala174) had a reduced total and nonrenal clearance, as compared with those with the OATP-C*1b allele (Asp130Val174); nonrenal clearance values in *1b/*1b (n = 4), *1b/*15 (n = 9), and *15/*15 (n = 1) subjects were 2.01 +/- 0.42 L. kg(-1). h(-1), 1.11 +/- 0.34 L. kg(-1). h(-1), and 0.29 L. kg(-1). h(-1), respectively, and the difference between *1b/*1b and *1b/*15 subjects was significant (P <.05).
Certain commonly occurring single-nucleotide polymorphisms in OATP-C, such as T521C (Val174Ala), are likely to be associated with altered pharmacokinetics of pravastatin. Large clinical studies are needed to confirm these observations.
Clinical Pharmacology & Therapeutics 06/2003; 73(6):554-65. · 6.04 Impact Factor
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Takeshi Hirota,
Ichiro Ieiri,
Hiroshi Takane,
Hiroyuki Sano,
Katsuyuki Kawamoto,
Hironao Aono,
Akira Yamasaki,
Hiromi Takeuchi,
Mikio Masada,
Eiji Shimizu,
Shun Higuchi,
Kenji Otsubo
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ABSTRACT: In this case report, we present genetic differences in two morphine-related gene sequences, UDP-glucuronosyltransferase 2B7 (UGT2B7) and mu opioid receptors (MOR1), in two cancer patients whose clinical responses to morphine were very different [i.e., sensitive (patient 1) and low responder (patient 2)]. In addition, allelic variants in the UGT2B7 gene were analyzed in 46 Japanese individuals. Amplified DNA fragments for the two genes of interest were screened using single strand conformation polymorphism and then sequenced. In the UGT2B7 gene, 12 single nucleotide polymorphisms (SNPs) were newly identified with an allelic frequency ranging from 0.022 to 0.978. Six SNPs in the promoter region (A-1302G, T-1295C, T-1111C, G-899A, A-327G, and T-125C) and two coding SNPs (UGT2B7*2 in exon 2 and C1059G in exon 4) appeared to be consistently linked. Remarkable differences in the nucleotide sequence of UGT2B7 were observed between the two patients; in contrast to patient 1 who had "reference" alleles at almost SNP positions, but a rare ATTGAT*2(AT)C haplotype as homozygosity, patient 2 was a homozygous carrier for the predominant GCCAGC*1(TC)G sequence. Serum morphine and two glucuronide concentrations in patient 2 suggest that the predominant GCCAGC*1G sequence was not associated with a "poor metabolizer" phenotype. In the MOR1 gene, patient 1 had no SNPs, whereas patient 2 was a heterozygous carrier for both the G-1784A and A118G alleles. The present study describes substantial differences in genotype patterns of two genes of interest between the two patients. The results necessitate larger trials to confirm these observations in larger case control studies.
Drug Metabolism and Disposition 06/2003; 31(5):677-80. · 3.73 Impact Factor
