Effects of carvedilol on MDR1 ‐mediated multidrug resistance: comparison with verapamil

Kakumoto, Mikio; Sakaeda, Toshiyuki; Takara, Kohji; Nakamura, Tsutomu; Kita, Tomoko; Yagami, Tatsurou; Kobayashi, Hironao; Okamura, Noboru; Okumura, Katsuhiko

doi:10.1111/j.1349-7006.2003.tb01356.x

Cited by 34 publications

(26 citation statements)

References 27 publications

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“…Thus, it is expected that MDR1 plays an important role in the pharmacokinetics of various types of structurally unrelated drugs. In addition, it has been demonstrated that MDR1 has been found to be a key protein for drug interaction, similarly to CYPs [59][60][61][62].…”

Section: What Is Mdr1?mentioning

confidence: 97%

Pharmacogenetics of Drug Transporters and Its Impact on the Pharmacotherapy

Sakaeda¹,

Nakamura²,

Okumura

2004

CTMC

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Most drug responses are determined by the interplay of several gene products that influence pharmacokinetics and pharmacodynamics, i.e., drug metabolizing enzymes, drug transporters, and drug targets. With the sequencing of the human genome, it has been estimated that approximately 500-1200 genes code for drug transporters. Concerning the effects of genetic polymorphisms on pharmacotherapy, the best characterized drug transporter is the multidrug resistant transporter P-glycoprotein/MDR1, the gene product of MDR1. Little such information is available on other drug transporters. MDR1 is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette superfamily, and is expressed mainly in intestines, liver, kidneys and brain. A number of various types of structurally unrelated drugs are substrates for MDR1, and their intestinal absorption, hepatobiliary secretion, renal secretion and brain transport are regulated by MDR1. The first investigation on the effects of MDR1 genotypes on pharmacotherapy was reported in 2000: a silent single nucleotide polymorphism (SNP), C3435T in exon 26, was found to be associated with the duodenal expression of MDR1, and thereby the plasma concentration of digoxin after oral administration. At present, a total of 28 SNPs have been found at 27 positions on the MDR1 gene. Clinical investigations on the association of MDR1 genotypes with the expression and function of MDR1 in tissues, and with pharmacokinetics and pharmacodynamics have mainly focused on C3435T; however, there are still discrepancies in the results, suggesting that the haplotype of the gene should be analyzed instead of a SNP. C3435T is also reported to be a risk factor for a certain class of diseases including the inflammatory bowel diseases, Parkinson's disease and renal epithelial tumor, and this also might be explained by the effects on MDR1 expression and function. In this review, the latest reports on the effects of genetic polymorphisms of MDR1 on pharmacotherapy are summarized, and the pharmacogenetics of other transporters is briefly introduced.

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Section: What Is Mdr1?mentioning

confidence: 97%

Pharmacogenetics of Drug Transporters and Its Impact on the Pharmacotherapy

Sakaeda¹,

Nakamura²,

Okumura

2004

CTMC

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“…• Inhibition of CYP 2D6 by nilotinib: 1 metoprolol exposure 9,18,19 Bisoprolol • Inhibition of CYP 2D6 by imatinib: 1 bisoprolol exposure 18 • Inhibition of CYP 3A4 by dasatinib: 1 bisoprolol exposure 9,18 • Inhibition of CYP 2D6 by nilotinib: 1 bisoprolol exposure 9,18,19 Carvedilol • Inhibition of CYP 2C9 and 2D6 by imatinib: 1 carvedilol exposure 18 • Inhibition of Pgp by carvedilol: 1 imatinib exposure 64,71,77 • Inhibition of Pgp by carvedilol: 1 dasatinib exposure 9,10,52,67,68,77…”

Section: Hmg-coa Reductase Inhibitorsmentioning

confidence: 99%

Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib

Haouala¹,

Widmer²,

Duchosal³

et al. 2011

Blood

215

147

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Several cancer treatments are shifting from traditional, time-limited, nonspecific cytotoxic chemotherapy cycles to continuous oral treatment with specific proteintargeted therapies. In this line, imatinib mesylate, a selective tyrosine kinases inhibitor (TKI), has excellent efficacy in the treatment of chronic myeloid leukemia. It has opened the way to the development of additional TKIs against chronic myeloid leukemia, including nilotinib and dasatinib. TKIs are prescribed for prolonged periods, often in patients with comorbidities. Therefore, they are regularly co-administered along with treatments at risk of drug-drug interactions. This aspect has been partially addressed so far, calling for a comprehensive review of the published data. We review here the available evidence and pharmacologic mechanisms of interactions between imatinib, dasatinib, and nilotinib and widely prescribed co-medications, including known inhibitors or inducers of cytochromes P450 or drug transporters. Information is mostly available for imatinib mesylate, well introduced in clinical practice. Several pharmacokinetic aspects yet remain insufficiently investigated for these drugs. Regular updates will be mandatory and so is the prospective reporting of unexpected clinical observations. (Blood. 2011;117(8):e75-e87)

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“…9 However, it has been demonstrated before that propranolol, metoprolol, and atenolol did not affect P-gp transport, 10 suggesting that the effects of carvedilol are independent of its actions on ␤-adrenoceptors. This was confirmed with our findings utilizing blood pressure and heart rate changes.…”

Section: Potential Mechanism Of Csa-carvedilol Interactionmentioning

confidence: 97%

“…However, recent reports have suggested that carvedilol, but not metoprolol, modulates P-glycoprotein (P-gp), a membrane protein that regulates CsA absorption. 9,10 The primary objective of this study was to compare the effects of carvedilol and metoprolol on CsA trough levels when initiated in cardiac transplant recipients.…”

mentioning

confidence: 99%