PURPOSE: To assess the contribution of drug metabolism to the variability on flavopiridol glucuronidation observed in cancer patients, and to determine the ability of all known human UDP-glucuronosyltransferase (UGT) isoforms to glucuronidate flavopiridol. METHODS: Inter-individual variation in flavopiridol glucuronidation was determined by HPLC using hepatic microsomes from 62 normal liver donors. Identification of enzymes capable of glucuronidating flavopiridol was determined by LC/MS using human embryonic kidney 293 (HEK293) cells stably expressing all sixteen known human UGTs. RESULTS: The major product of the flavopiridol glucuronidation reaction in human liver microsomes was FLAVO-7-G. High variability (coefficient of variation = 49%) was observed in the glucuronidation of flavopiridol by human liver microsomes. In vitro formation of FLAVO-7-G and FLAVO-5-G was mainly catalyzed by UGT1A9 and UGT1A4, respectively. Similar catalytic efficiencies (Vmax/Km) were observed for human liver microsomes (1.6 microl/min/mg) and UGT1A9 (1.5 microl/min/mg). CONCLUSIONS: UGT1A9 is the major UGT involved in the hepatic glucuronidation of flavopiridol in humans. The data suggests that hepatic glucuronidation may be a major determinant of the variable systemic glucuronidation of flavopiridol in cancer patients. The large variability in flavopiridol glucuronidation may be due to differences in liver metabolism among individuals, as a result of genetic differences in UGT1A9.
PURPOSE: To assess the contribution of drug metabolism to the variability on flavopiridol glucuronidation observed in cancerpatients, and to determine the ability of all known humanUDP-glucuronosyltransferase (UGT) isoforms to glucuronidate flavopiridol. METHODS: Inter-individual variation in flavopiridol glucuronidation was determined by HPLC using hepatic microsomes from 62 normal liver donors. Identification of enzymes capable of glucuronidating flavopiridol was determined by LC/MS using humanembryonic kidney 293 (HEK293) cells stably expressing all sixteen known human UGTs. RESULTS: The major product of the flavopiridol glucuronidation reaction in human liver microsomes was FLAVO-7-G. High variability (coefficient of variation = 49%) was observed in the glucuronidation of flavopiridol by human liver microsomes. In vitro formation of FLAVO-7-G and FLAVO-5-G was mainly catalyzed by UGT1A9 and UGT1A4, respectively. Similar catalytic efficiencies (Vmax/Km) were observed for human liver microsomes (1.6 microl/min/mg) and UGT1A9 (1.5 microl/min/mg). CONCLUSIONS:UGT1A9 is the major UGT involved in the hepatic glucuronidation of flavopiridol in humans. The data suggests that hepatic glucuronidation may be a major determinant of the variable systemic glucuronidation of flavopiridol in cancerpatients. The large variability in flavopiridol glucuronidation may be due to differences in liver metabolism among individuals, as a result of genetic differences in UGT1A9.
Authors: A M Senderowicz; D Headlee; S F Stinson; R M Lush; N Kalil; L Villalba; K Hill; S M Steinberg; W D Figg; A Tompkins; S G Arbuck; E A Sausville Journal: J Clin Oncol Date: 1998-09 Impact factor: 44.544
Authors: B Hagenauer; A Salamon; T Thalhammer; O Kunert; E Haslinger; P Klingler; A M Senderowicz; E A Sausville; W Jäger Journal: Drug Metab Dispos Date: 2001-04 Impact factor: 3.922
Authors: William Blum; Mitch A Phelps; Rebecca B Klisovic; Darlene M Rozewski; Wenjun Ni; Katie A Albanese; Brad Rovin; Cheryl Kefauver; Steven M Devine; David M Lucas; Amy Johnson; Larry J Schaaf; John C Byrd; Guido Marcucci; Michael R Grever Journal: Haematologica Date: 2010-05-11 Impact factor: 9.941
Authors: Wenjun Ni; Jia Ji; Zunyan Dai; Audrey Papp; Amy J Johnson; Sunjoo Ahn; Katherine L Farley; Thomas S Lin; James T Dalton; Xiaobai Li; David Jarjoura; John C Byrd; Wolfgang Sadee; Michael R Grever; Mitch A Phelps Journal: PLoS One Date: 2010-11-01 Impact factor: 3.240
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: Pharmacogenet Genomics Date: 2013-07 Impact factor: 2.089
Authors: Jia Ji; Diane R Mould; Kristie A Blum; Amy S Ruppert; Ming Poi; Yuan Zhao; Amy J Johnson; John C Byrd; Michael R Grever; Mitch A Phelps Journal: Clin Cancer Res Date: 2013-01-08 Impact factor: 12.531
Authors: Beata Holkova; Jeffrey G Supko; Matthew M Ames; Joel M Reid; Geoffrey I Shapiro; Edward Brent Perkins; Viswanathan Ramakrishnan; Mary Beth Tombes; Connie Honeycutt; Renee M McGovern; Maciej Kmieciak; Ellen Shrader; Martha D Wellons; Heidi Sankala; Austin Doyle; John Wright; John D Roberts; Steven Grant Journal: Clin Cancer Res Date: 2013-03-20 Impact factor: 12.531
Authors: R W Robey; Y Honjo; K Morisaki; T A Nadjem; S Runge; M Risbood; M S Poruchynsky; S E Bates Journal: Br J Cancer Date: 2003-11-17 Impact factor: 7.640