Abstract | OBJECTIVE:
ABT-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. METHODS: RESULTS: UGT1A1, 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). CONCLUSION: These 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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Authors | Federico Innocenti, Jacqueline Ramírez, Jennifer Obel, Julia Xiong, Snezana Mirkov, Yi-Lin Chiu, David A Katz, Robert A Carr, Wei Zhang, Soma Das, Araba Adjei, Ann M Moyer, Pei Xian Chen, Andrew Krivoshik, Diane Medina, Gary B Gordon, Mark J Ratain, Leonardo Sahelijo, Richard M Weinshilboum, Gini F Fleming, Anahita Bhathena |
Journal | Pharmacogenetics and genomics
(Pharmacogenet Genomics)
Vol. 23
Issue 7
Pg. 374-81
(Jul 2013)
ISSN: 1744-6880 [Electronic] United States |
PMID | 23670235
(Publication Type: Clinical Trial, Phase I, Journal Article)
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Chemical References |
- ABT751
- Antineoplastic Agents
- Sulfonamides
- Tubulin Modulators
- bilirubin glucuronoside glucuronosyltransferase
- Glucuronosyltransferase
- Sulfotransferases
- Arylsulfotransferase
- SULT1A1 protein, human
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Topics |
- Adult
- Aged
- Antineoplastic Agents
(pharmacokinetics)
- Arylsulfotransferase
(genetics)
- Female
- Gene Dosage
- Genetic Variation
- Glucuronosyltransferase
(genetics, metabolism)
- Humans
- Male
- Middle Aged
- Sulfonamides
(pharmacokinetics)
- Sulfotransferases
(genetics, metabolism)
- Tubulin Modulators
(pharmacokinetics)
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