ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

Leschziner, Guy; Andrew, Toby; Pirmohamed, Munir; Johnson, Michael R.

doi:10.1038/sj.tpj.6500413

Cited by 260 publications

(230 citation statements)

References 120 publications

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“…37 For the uptake transporters OATP 1B3 and OATP 1B1 we selected missense polymorphisms with reported functional consequences. 17 Finally, for ABCB1 we selected the three most studied variants (1236C4T, 2677G4T and 3435C4T) 27 associated with altered transport and a missense (N21D) polymorphism described in public databases but not previously studied.…”

Section: Patientsmentioning

confidence: 99%

“…23,24 The genes encoding these proteins are subjected to relevant genetic variation, which can alter drug metabolism and disposition, as we and others have shown. 17,[25][26][27] At present, despite its potential importance for neurotoxicity, very little is known about the genes responsible for the final concentration of paclitaxel and its metabolites in the nervous cells. The association between paclitaxel neurotoxicity and pharmacokinetic parameters 11,15 leads us to propose that polymorphisms in the genes mediating paclitaxel elimination could contribute to the interindividual differences in this toxicity.…”

Section: Introductionmentioning

confidence: 99%

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Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

et al. 2010

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Neurotoxicity is one of the most relevant dose-limiting toxicities of the anticancer drug paclitaxel. It exhibits substantial interindividual variability of unknown molecular basis, and represents one of the major challenges for the improvement of paclitaxel therapy. The extensive variability in paclitaxel clearance and metabolism lead us to investigate the association between polymorphisms in paclitaxel elimination pathway and neurotoxicity. We selected 13 relevant polymorphisms in genes encoding paclitaxel metabolizing enzymes (CYP2C8, CYP3A4 and CYP3A5) and transporters (organic anion transporting polypeptide (OATP) 1B1, OATP1B3 and P-glycoprotein) and genotyped them in 118 Spanish cancer patients treated with paclitaxel. After adjusting for age and treatment schedule, CYP2C8 Haplotype C and CYP3A5*3 were associated with protection (hazard ratio (HR) (per allele) ¼ 0.55; 95% confidence interval (CI) ¼ 0.34-0.89; P ¼ 0.014 and HR (per allele) ¼ 0.51; 95%CI ¼ 0.30-0.86; and P ¼ 0.012, respectively) and CYP2C8*3 with increased risk (HR (per allele) ¼ 1.72; 95%CI ¼ 1.05-2.82; and P ¼ 0.032). In each case, the allele causing increased paclitaxel metabolism was associated with increased neurotoxicity, suggesting an important role for metabolism and hydroxylated paclitaxel metabolites. We estimated the HR per paclitaxel-metabolism increasing allele carried across the three polymorphisms to be HR ¼ 1.64 (95% CI ¼ 1.26-2.14; P ¼ 0.0003). The results for P-glycoprotein were inconclusive, and no associations were observed for the other genes studied. The incorporation of this genetic data in treatment selection could help to reduce neurotoxicity events, thereby individualizing paclitaxel pharmacotherapy. These results warrant validation in independent series.

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Section: Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

et al. 2010

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“…MDR1 gene encodes for the ATPdependent membrane efflux transport for p-glycoprotein, and it was shown that MDR1 polymorphisms could affect the pharmacokinetics of digoxin [30,31]. The P-gp acts as a pump to remove substrates from inside to the outside of the cell.…”

Section: Atrial Fibrillation Digoxinmentioning

confidence: 99%

“…The P-gp acts as a pump to remove substrates from inside to the outside of the cell. It is expressed in several human tissues such as the liver, kidney, small and large intestine, brain, placenta, and adrenal glands [31].…”

Section: Atrial Fibrillation Digoxinmentioning

confidence: 99%

Pharmacogenomics: The Significance of Genetics in the Metabolism of Natural Medicines

Hanna¹

2012

JBNB

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Natural products have been implemented in medicine through use as herbal medications, chemical compound extraction for prescription medication, or a natural source of food to fight various infections and diseases. Genetics has played a role in identifying various interactions between existing drugs and side effects. In addition, various food allergies have been identified with children in recent years, suggesting genetic associations between certain populations carrying specific genetic alleles. The recent availability of genomic data and our increased understanding of the effects of genetic variations permit a quantitative examination of the contribution of genetic variation to efficacy or toxicity of compounds derived from natural sources. The identification of target molecules relevant for diseases allows screening for natural products capable of inhibiting targets which can lead to the development of rational treatment of various diseases including neurobiological disorders, cancer, osteoporosis, and cardiovascular diseases. This allows for more opportunities to predict the response of individual patients. Identification of genetic variations that arose as a consequence of naturally occurring compounds will help identify gene alleles, or protein ligands that can affect the pharmacodynamic and pharmacokinetics of the natural products in question. In addition, diet modification and precautions to food products can be identified to help consumers limit or increase certain food intake. Understanding the molecular mechanisms underlying these interactions and their modification by genetic variation is expected to result in the development of new drugs that optimize individual health. We expect that strategies for individualized therapies will lead to improved results for patients.

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“…Saturation of the multidrug transporter by high concentrations of gefitinib at the apical surface of the intestinal epithelial cells may explain these results. Moreover, the functional effect of the variant tested is controversial, with conflicting results throughout the literature [51]. In addition, phenytoin is a well-known P-gp inducer, in addition to CYP3A4 [52].…”

Section: Figurementioning

confidence: 99%

Gefitinib–phenytoin interaction is not correlated with the ¹⁴C‐erythromycin breath test in healthy male volunteers

Chhun

Verstuyft

Rizzo-Padoin

et al. 2009

Brit J Clinical Pharma

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AIMSWe aimed to describe the pharmacokinetic interaction between phenytoin, a potent CYP3A4 and P-glycoprotein (P-gp) (ABCB1) inducer, and gefitinib, a CYP3A4, CYP2D6 and P-gp substrate. METHODSAn open-label, randomized, two-phase crossover study was conducted. Eighteen healthy male volunteers (nine homozygous CC and nine homozygous TT as determined by their ABCB1 C3435T polymorphism in exon 26) received a single oral dose of 250 mg gefitinib alone or after 5 days treatment with phenytoin (5 mg kg -1 daily). Gefitinib plasma concentrations were determined by high-performance liquid chromatography. Hepatic CYP3A4 activity was evaluated by the 14 C-erythromycin breath test (ERMBT) and the ABCB1 and CYP2D6 genetic polymorphisms were determined by the TaqMan allelic discrimination assay and long polymerase chain reaction, respectively. RESULTSFollowing treatment with phenytoin, mean gefitinib Cmax and AUC0-• decreased by 26 Ϯ 44% [95% confidence interval (CI) for the difference 5-48%, P = 0.005] and 47 Ϯ 26% (95% CI for the difference 34-60%, P = 0.001), respectively, and apparent oral clearance increased by 126 Ϯ 93% (95% CI for the difference 80-172%, P = 0.004). Concomitantly, phenytoin increased the mean ERMBT by 91 Ϯ 44% (95% CI 75-105%, P < 0.001) from baseline, but the extent of liver CYP3A4 induction was not correlated to the extent of interaction. Furthermore, this interaction was independent of ABCB1 genetic polymorphism. The CYP2D6 genotype was slightly but significantly related to gefitinib clearance (P = 0.04) during the control phase. CONCLUSIONSThe significant interaction between gefitinib and phenytoin was not correlated with the erythromycin breath test and was independent of ABCB1 polymorphism, but may involve presystemic CYP3A-mediated intestinal first-pass.British Journal of Clinical Pharmacology DOI:10.1111DOI:10. /j.1365DOI:10. -2125DOI:10. .2009 226 / Br J Clin Pharmacol / 68:2 / 226-237 IntroductionGefitinib (ZD 1839) is the first available oral quinazoline compound referred to as a 'selective' epidermal growth factor (EGF) receptor-tyrosine kinase inhibitor [1]. It provides an antiproliferative effect by blocking signal transduction from the EGF receptor and has been recently approved as third-line monotherapy in Japan for the treatment of cancer patients who present with locally advanced inoperable or recurrent non-small cell lung carcinoma. Gefitinib systemic exposure is rather complex and highly variable between subjects [1]. Gefitinib is a high-extraction drug with a mean volume of distribution of about 1500 l in humans and is subject to complex and extensive presystemic first-pass [1]. Drug-transport proteins including P-glycoprotein (P-gp) and drug-metabolizing enzymes, e.g. cytochromes P450 (CYP), are relevant factors affecting the pharmacokinetic profile of gefitinib. Preclinical studies performed with human liver microsomes suggested that CYP3A4 was the major enzyme involved in gefitinib metabolism.The 3A4 isoform accounts for as much as 35% of total CYPs expressed in the liver and...

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ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

Cited by 260 publications

References 120 publications

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

Pharmacogenomics: The Significance of Genetics in the Metabolism of Natural Medicines

Gefitinib–phenytoin interaction is not correlated with the ¹⁴C‐erythromycin breath test in healthy male volunteers

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ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

Cited by 260 publications

References 120 publications

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

Pharmacogenomics: The Significance of Genetics in the Metabolism of Natural Medicines

Gefitinib–phenytoin interaction is not correlated with the 14C‐erythromycin breath test in healthy male volunteers

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Gefitinib–phenytoin interaction is not correlated with the ¹⁴C‐erythromycin breath test in healthy male volunteers