PURPOSE: Ketoconazole has been shown to inhibit the glucuronidation of the UGT2B7 substrates zidovudine and lorazepam. Its effect on UGT1A substrates is unclear. A recent study found that coadministration of irinotecan and ketoconazole led to a significant increase in the formation of SN-38 (7-ethyl-10-hydroxycamptothecine), an UGT1A substrate. This study investigates whether ketoconazole contributes to the increase in SN-38 formation by inhibiting SN-38 glucuronidation. EXPERIMENTAL DESIGN: SN-38 glucuronidation activities were determined by measuring the rate of SN-38 glucuronide (SN-38G) formation using pooled human liver microsomes and cDNA-expressed UGT1A isoforms (1A1, 1A7 and 1A9) in the presence of ketoconazole. Indinavir, a known UGT1A1 inhibitor, was used as a positive control. SN-38G formation was measured by high-performance liquid chromatograph. RESULTS: Ketoconazole competitively inhibited SN-38 glucuronidation. Among the UGT1A isoforms screened, ketoconazole showed the highest inhibitory effect on UGT1A1 and UGT1A9. The K(i) values were 3.3 +/- 0.8 micromol/L for UGT1A1 and 31.9 +/- 3.3 micromol/L for UGT1A9. CONCLUSIONS: These results show that ketoconazole is a potent UGT1A1 inhibitor, which seems the basis for increased exposure to SN-38 when coadministered with irinotecan.
PURPOSE:Ketoconazole has been shown to inhibit the glucuronidation of the UGT2B7 substrates zidovudine and lorazepam. Its effect on UGT1A substrates is unclear. A recent study found that coadministration of irinotecan and ketoconazole led to a significant increase in the formation of SN-38 (7-ethyl-10-hydroxycamptothecine), an UGT1A substrate. This study investigates whether ketoconazole contributes to the increase in SN-38 formation by inhibiting SN-38 glucuronidation. EXPERIMENTAL DESIGN:SN-38 glucuronidation activities were determined by measuring the rate of SN-38 glucuronide (SN-38G) formation using pooled human liver microsomes and cDNA-expressed UGT1A isoforms (1A1, 1A7 and 1A9) in the presence of ketoconazole. Indinavir, a known UGT1A1 inhibitor, was used as a positive control. SN-38G formation was measured by high-performance liquid chromatograph. RESULTS:Ketoconazole competitively inhibited SN-38 glucuronidation. Among the UGT1A isoforms screened, ketoconazole showed the highest inhibitory effect on UGT1A1 and UGT1A9. The K(i) values were 3.3 +/- 0.8 micromol/L for UGT1A1 and 31.9 +/- 3.3 micromol/L for UGT1A9. CONCLUSIONS: These results show that ketoconazole is a potent UGT1A1 inhibitor, which seems the basis for increased exposure to SN-38 when coadministered with irinotecan.
Authors: Kuresh A Youdim; Aref Zayed; Maurice Dickins; Alex Phipps; Michelle Griffiths; Amanda Darekar; Ruth Hyland; Odette Fahmi; Susan Hurst; David R Plowchalk; Jack Cook; Feng Guo; R Scott Obach Journal: Br J Clin Pharmacol Date: 2008-02-14 Impact factor: 4.335
Authors: Sabrina Jones; Azure L Yarbrough; Amal Shoeib; John M Bush; William E Fantegrossi; Paul L Prather; Anna Radominska-Pandya; Ryoichi Fujiwara Journal: Xenobiotica Date: 2019-03-20 Impact factor: 1.908
Authors: Jennifer Lee; Selina Moy; John Meijer; Walter Krauwinkel; Taiji Sawamoto; Virginie Kerbusch; Donna Kowalski; Michael Roy; Alan Marion; Shin Takusagawa; Marcel van Gelderen; James Keirns Journal: Clin Drug Investig Date: 2013-06 Impact factor: 2.859
Authors: Eric I Zimmerman; Justin L Roberts; Lie Li; David Finkelstein; Alice Gibson; Amarjit S Chaudhry; Erin G Schuetz; Jeffrey E Rubnitz; Hiroto Inaba; Sharyn D Baker Journal: Clin Cancer Res Date: 2012-08-27 Impact factor: 12.531