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Inhibition of SN‐38 glucuronidation by ketoconazole
Author(s) -
Yong W.,
Ramirez J.,
Innocenti F.,
Ratain M. J.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.176
Subject(s) - ketoconazole , glucuronidation , pharmacology , chemistry , microsome , ugt2b7 , active metabolite , glucuronide , sn 38 , irinotecan , ic50 , metabolite , pharmacokinetics , biochemistry , biology , medicine , in vitro , colorectal cancer , antifungal , cancer , microbiology and biotechnology
Background/Aims Ketoconazole has been shown to inhibit the glucuronidation of the UGT2B7 substrates AZT and lorazepam. Its effect on UGT1A substrates is unknown. A recent study (Kehrer et al, JClin Oncol, 2002) found that co‐administration of irinotecan and ketoconazole led to a significant increase in the formation of SN‐38. This study investigates whether ketoconazole contributes to the increase in SN‐38 formation by inhibiting SN‐38 glucuronidation. Methods SN‐38 glucuronidation activities were determined by measuring the rate of SN‐38 glucuronide (SN‐38G) formation using pooled human liver microsomes (HLM) and cDNA transfected UGT1A isoforms (1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9) in the presence of ketoconazole. Indinavir, a known UGT1A1 inhibitor, was used as a positive control. SN‐38G formation was measured by HPLC. Results A 20% reduction in SN‐38G formation was observed after incubation of HLM with SN‐38 and ketoconazole at 10 μM (p=0.001). Among the UGT1A isoforms screened, ketoconazole showed the highest inhibitory effect on UGT1A1 and UGT1A9, reducing SN‐38 glucuronidation activities by 59% and 32% (p<0.05), respectively. The IC50 values (using UGT1A1 and UGT1A9) were 8.8 μM and 6.3 μM for ketoconazole, respectively. Conclusion These results suggest that ketoconazole is a potent UGT1A1 and UGT1A9 inhibitor. Further work is currently being undertaken to establish the possible mechanism of ketoconazole‐mediated inhibition of SN‐38 glucuronidation. Clinical Pharmacology & Therapeutics (2005) 77 , P75–P75; doi: 10.1016/j.clpt.2004.12.176