Abstract
ABT-751 is an oral antimitotic agent in phase 2 development. In cancer patients, ABT-751 is extensively metabolized by glucuronidation and sulfation. To identify the UGT isoforms involved in ABT-751 glucuronidation, we have determined maximum turnover (Vmax) and affinity constant (Km) of pooled human liver microsomes (HLMs) and commercially available human UDP-glucuronosyltransferases (UGTs, 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, 2B17) for ABT-751. Formation of ABT-751 glucuronide was measured by HPLC. The kinetic properties of ABT-751 glucuronidation in HLM and the UGTs with the highest Vmax/Km values are shown below: (See Table) Other UGTs showed considerably lower and slower production of ABT-751 glucuronide. Our data suggest that 1A8, 1A4, 1A1 and 2B7 are the main isoforms responsible for ABT-751 glucuronidation. 1A8 is expressed in the intestinal tract and might be involved in ABT-751 absorption. 1A4, 1A1 and 2B7 are expressed in the liver and gastrointestinal tract and so might also be involved in ABT-751 hepatic metabolism. Future studies will evaluate the effect of 1A8, 1A4, 1A1 and 2B7 gene variation on ABT-751 pharmacokinetics in cancer patients. We are conducting similar experiments to identify the sulfotransferases involved in ABT-751 sulfation. Clinical Pharmacology & Therapeutics (2004) 75, P86–P86; doi: 10.1016/j.clpt.2003.11.328 Vmax (pmol/min/mg) (mean±SE) Km(μM) (mean±SE) Vmax/Km (μl/min/mg) HLM (pooled) 150.9 ± 6.5 114.2 ± 16.2 1.3 1A1 60.0 ± 1.7 82.8 ± 7.8 0.7 1A4 54.3 ± 1.5 43.3 ± 5.3 1.3 1A8 141.9 ± 5.7 36.7 ± 7.1 3.9 2B7 41.8 ± 0.8 58.4 ± 4.5 0.7
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