65686-11-5Relevant academic research and scientific papers
Expression and characterization of cynomolgus monkey cytochrome cyp3a4 in a novel human embryonic kidney cell-based mammalian systems
Selvakumar, Sindhuja,Bhutani, Priyadeep,Ghosh, Kaushik,Krishnamurthy, Prasad,Kallipatti, Sanjith,Selvam, Sabariya,Ramarao, Manjunath,Mandlekar, Sandhya,Sinz, Michael W.,Rodrigues, A. David,Subramanian, Murali
, p. 369 - 376 (2014/03/21)
Cynomolgus monkeys are a commonly used species in preclinical drug discovery, and have high genetic similarity to humans, especially for the drug-metabolizing cytochrome P450s. However, species differences are frequently observed in the metabolism of drug
Prediction of metabolic clearance using fresh human hepatocytes: Comparison with cryopreserved hepatocytes and hepatic microsomes for five benzodiazepines
Hallifax,Galetin,Houston
, p. 353 - 367 (2008/12/21)
1. Predictions of in vivo intrinsic clearance from cryopreserved human hepatocytes may be systematically low. In the current study, the metabolite kinetics of a series of CYP3A4 substrates (benzodiazepines) in fresh human hepatocytes from five donors, via a major UK supplier, were investigated and compared with those previously reported (by the authors' laboratory) for cryopreserved human hepatocytes and hepatic microsomes. 2. A high incidence of autoactivation (up to tenfold) and heteroactivation (by testosterone, up to 14-fold) among the major pathways was observed. CYP capacity (Vmax) was marginally lower and 'affinity' constants (KM, S50) were marginally greater compared with cryopreserved hepatocytes. 3. Average intrinsic clearance (based on maximal clearance, CLmax) was sevenfold lower than in cryopreserved hepatocytes (reflecting sensitivity of intrinsic clearance estimation in vitro to mechanistic parameter values, particularly those involving atypical kinetics), but scaled intrinsic clearances for fresh (and cryopreserved) hepatocytes were within the range previously determined in hepatic microsomes. 4. There was no evidence from this series of studies that fresh hepatocytes provide quantitatively improved estimates of intrinsic clearance over cryopreserved hepatocytes.
