ArticlePharmacogenetics and genomics2013
Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751.
Article in Pharmacogenetics and genomics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Expanding biobank pharmacogenomics through machine learning calls of structural variation.Genetics · 2025Article
- Serum anti-inflammatory and inflammatory markers have no causal impact on telomere length: a Mendelian randomization study.Archives of medical science : AMS · 2021Article
- Genetic Polymorphisms of Very Important Pharmacogene Variants in the Blang Population from Yunnan Province in China.Pharmacogenomics and personalized medicine · 2021Article
- Influence of genetic variants and antiepileptic drug co-treatment on lamotrigine plasma concentration in Mexican Mestizo patients with epilepsy.The pharmacogenomics journal · 2020Article
- Effect of genetic variation in UGT1A and ABCB1 on moxifloxacin pharmacokinetics in South African patients with tuberculosis.Pharmacogenomics · 2018Article
- Race, Gender, and Genetic Polymorphism Contribute to Variability in Acetaminophen Pharmacokinetics, Metabolism, and Protein-Adduct Concentrations in Healthy African-American and European-American Volunteers.The Journal of pharmacology and experimental therapeutics · 2017Article
- Phase 1 Study of ABT-751 in Combination With CAPIRI (Capecitabine and Irinotecan) and Bevacizumab in Patients With Advanced Colorectal Cancer.Journal of clinical pharmacology · 2016Article
- UGT1A and UGT2B genetic variation alters nicotine and nitrosamine glucuronidation in european and african american smokers.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2015Article
- Pharmacogenetics of SULT1A1.Pharmacogenomics · 2014Article
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21 authors.
Funding
Abstract
objectiveABT-751, a novel orally available antitubulin agent, is mainly eliminated as inactive glucuronide (ABT-751G) and sulfate (ABT-751S) conjugates. We performed a pharmacogenetic investigation of ABT-751 pharmacokinetics using in-vitro data to guide the selection of genes for genotyping in a phase I trial of ABT-751.
methodsUDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes were screened for ABT-751 metabolite formation in vitro. Forty-seven cancer patients treated with ABT-751 were genotyped for 21 variants in these genes.
resultsUGT1A1, UGT1A4, UGT1A8, UGT2B7, and SULT1A1 were found to be involved in the formation of inactive ABT-751 glucuronide (ABT-751G) and sulfate (ABT-751S). SULT1A1 copy number (>2) was associated with an average 34% increase in ABT-751 clearance (P=0.044), an 18% reduction in ABT-751 AUC (P=0.045), and a 50% increase in sulfation metabolic ratios (P=0.025). UGT1A8 rs6431558 was associated with a 28% increase in glucuronidation metabolic ratios (P=0.022), and UGT1A4*2 was associated with a 65% decrease in ABT-751 C trough (P=0.009).
conclusionThese results might represent the first example of a clinical pharmacokinetic effect of the SULT1A1 copy number variant on the clearance of a SULT1A1 substrate. A-priori selection of candidate genes guided by in-vitro metabolic screening enhanced our ability to identify genetic determinants of interpatient pharmacokinetic variability.
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