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Sakaeda, Toshiyuki; Nakamura, Tsutomu; Horinouchi, Masanori; Kakumoto, Mikio; Ohmoto, Nobuko; Sakai, Toshiyuki; Morita, Yoshinori; Tamura, Takao; Aoyama, Nobuo; Hirai, Midori; Kasuga, Masato; Okumura, Katsuhiko

doi:10.1023/a:1012244520615

Cited by 286 publications

(35 citation statements)

References 16 publications

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“…3). 57) This result agreed with our results on MDR1 mRNA levels in the biopsy specimens of duodenum (Fig. 1).…”

Section: )supporting

confidence: 93%

“…Interethnic differences in allele and genotype frequencies of C3435T are summarized in Table 3. [53][54][55][56][57] Few homozygotes for the T-allele (T/T 3435 ) were found with about 80% of individuals homozygotic for the C-allele (C/C 3435 ) in Ghanaian, Kenyan, African American and Sudanese populations, whereas T-allele frequencies were almost 50% for Caucasians and Asians.…”

Section: Mdr1mentioning

confidence: 99%

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MDR1 Genotype-Related Pharmacokinetics and Pharmacodynamics.

Sakaeda

Nakamura

Okumura

2002

Biological & Pharmaceutical Bulletin

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173

110

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The multidrug resistant transporter MDR1/P-glycoprotein, the gene product of MDR1, is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette superfamily of membrane transporters. MDR1 acts as an energy-dependent efflux pump that exports its substrates out of cells. MDR1 was originally isolated from resistant tumor cells as part of the mechanism of multidrug resistance, but over the last decade, it has been elucidated that human MDR1 is also expressed throughout the body to confer intrinsic resistance to the tissues by exporting unnecessary or toxic exogeneous substances or metabolites. A number of structurally unrelated drugs are substrates for MDR1, and MDR1 and other transporters are recognized as an important class of proteins for regulating pharmacokinetics and pharmacodynamics. In 2000, Hoffmeyer et al. performed a systemic screening for MDR1 polymorphisms and detected 15 single nucleotide polymorphisms (SNPs). They also indicated that a polymorphism in exon 26 at position 3435 (C3435T), a silent mutation, affected the expression level of MDR1 protein in duodenum, and thereby the intestinal absorption of digoxin. To date, the genotype frequencies of C3435T have been investigated extensively using a larger population and interethnic difference has been elucidated, and a total of 28 SNPs have been found at 27 positions on the MDR1 gene. Clinical studies on MDR1 genotype-related MDR1 expression and pharmacokinetics have also been performed around the world; however, results were not always consistent with Hoffmeyer's report. In this review, published reports are summarized for the future individualization of pharmacotherapy based on MDR1 genotyping. In addition, recent investigations have raised the possibility that MDR1 and related transporters play a fundamental role in regulating apoptosis and immunology, and in fact, there are reports of MDR1-related susceptibility to inflammatory bowel disease, HIV infection and renal cell carcinoma. Herein, these issues are also summarized, and the current status of the knowledge in the area of pharmacogenomics of other transporters is briefly introduced.

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“…3). 57) This result agreed with our results on MDR1 mRNA levels in the biopsy specimens of duodenum (Fig. 1).…”

Section: )supporting

confidence: 93%

Section: Mdr1mentioning

confidence: 99%

MDR1 Genotype-Related Pharmacokinetics and Pharmacodynamics.

Sakaeda

Nakamura

Okumura

2002

Biological & Pharmaceutical Bulletin

Self Cite

173

110

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“…16,17) The genotypes of T-129C, G2677A,T and C3435T of the MDR1 gene were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis as described before 16,17) and confirmed by direct sequencing. Herein, C1236T was also determined by direct sequencing according to the report by Kim et al 18) The gene product of MDR1 is the multi-drug resistant transporter MDR1/P-glycoprotein, a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette superfamily of membrane transporters.…”

Section: Steroid Therapy For Relapses Of Ns or Slementioning

confidence: 99%

Association of Cumulative Cyclosporine Dose with Its Irreversible Nephrotoxicity in Japanese Patients with Pediatric-Onset Autoimmune Diseases

Nakamura

Nozu

Iijima

et al. 2007

Biological & Pharmaceutical Bulletin

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“…24) Greiner et al reported that the expression level of the MDR1 gene affects the plasma clearance of digoxin after oral administration. 25) Furthermore, Goto et al suggests that the MDR1 C3435T polymorphism correlates with the intestinal expression level of CYP3A4.…”

Section: Subjects and Study Protocolsmentioning

confidence: 99%

“…25) Assay of Carvedilol The blood concentration of carvedilol was measured using chiral high performance liquid chromatography (HPLC) as described by Mihara et al with minor modifications. 8,27) Briefly, whole blood samples (0.2 ml) were mixed with 0.5 ml of distilled water to hemolyze the blood cells.…”

Section: Subjects and Study Protocolsmentioning

confidence: 99%

Multiple Regression Analysis of Pharmacogenetic Variability of Carvedilol Disposition in 54 Healthy Japanese Volunteers

Honda

Ogura

Toyoda

et al. 2006

Biological & Pharmaceutical Bulletin

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Carvedilol is a b-adrenoceptor antagonist used clinically to treat chronic heart failure as well as hypertension, angina pectoris, and cardiac arrhythmias.1-4) Carvedilol is highly lipophilic and eliminated predominantly by hepatic metabolism, with renal excretion accounting for only 0.3% of the administered dose.5) The drug is absorbed rapidly from the gastrointestinal tract after oral administration; however, the amount of unchanged drug excreted in the feces was 23% of the administered dose probably because of incomplete intestinal absorption.6) In addition, orally administered carvedilol undergoes stereoselective first-pass metabolism, and the maximal plasma concentration of R-enantiomer with low bblocking activity is approximately 2-fold higher than that of S-enantiomer with high b-blocking activity.6) The mean absolute bioavailability of R-and S-enantiomer in humans is 31% and 15%, respectively. 7)In the previous study, we investigated the effect of genetic polymorphisms of cytochrome P450 (CYP) 2D6 on the pharmacokinetics of R-and S-carvedilol in 23 healthy Japanese volunteers.8) The large interindividual variability was observed in the pharmacokinetics of carvedilol, and the coefficient of variation of the weight (WT)-corrected oral clearance ((CL/F)/ WT) value among the subjects was 36.1%. In addition, the (CL/F)/WT value was highly correlated with the apparent distribution volume ((V/F)/WT) value among the subjects, suggesting that the interindividual difference in bioavailability (F) was at least partly responsible for the pharmacokinetic variability of carvedilol. The (CL/F)/WT and (V/F)/WT values of R-and S-carvedilol were significantly lower in healthy volunteers with at least one CYP2D6*10 allele than those with the CYP2D6*1/*1 and *1/*2 genotype. The result suggested that the systemic and/or pre-systemic metabolism of R-and S-carvedilol in the liver is significantly decreased in Japanese subjects with the CYP2D6*10 allele.Carvedilol is metabolized extensively via aliphatic sidechain oxidation and conjugation pathways, as well as the aromatic ring oxidation pathway which is mediated mainly by CYP2D6. 6) Oldham et al. reported that considerable metabolic activity for carvedilol is observed in CYP1A2, 2C9, 2D6, and 3A4. 9) On the other hand, it is still unclear whether the other P450s are involved in the metabolism of carvedilol. However, a substrate of CYP2C9, such as phenytoin, is partly catalyzed by another CYP2C subfamily, CYP2C19. 10)CYP3A5 is another important CYP3A protein in the liver, the substrate specificity of which largely overlaps with that of CYP3A4.11) In addition, Ohno et al. reported that UDP-glucuronosyltransferase (UGT) 1A1, 2B4, and 2B7 as well as human hepatic microsomes are capable of catalyzing the glucuronidation of carvedilol.12) Moreover, carvedilol has high affinity for the multidrug resistance 1 (MDR1) gene product P-glycoprotein (P-gp). Giessmann et al. reported that the intestinal expression of P-gp is a major variable in the disposition of carvedilol. 13)In the presen...

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Abstract: The serum concentration of digoxin after single oral administration was lower in the subjects harboring a mutant allele (C3435T) at exon 26 of the MDR1 gene.

Cited by 286 publications

References 16 publications

MDR1 Genotype-Related Pharmacokinetics and Pharmacodynamics.

MDR1 Genotype-Related Pharmacokinetics and Pharmacodynamics.

Association of Cumulative Cyclosporine Dose with Its Irreversible Nephrotoxicity in Japanese Patients with Pediatric-Onset Autoimmune Diseases

Multiple Regression Analysis of Pharmacogenetic Variability of Carvedilol Disposition in 54 Healthy Japanese Volunteers

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