Document Detail

Effect of Albumin on Human Liver Microsomal and Recombinant CYP1A2 Activities: Impact on In Vitro - In Vivo Extrapolation of Drug Clearance.
MedLine Citation:
PMID:  22331994     Owner:  NLM     Status:  Publisher    
Long chain unsaturated fatty acids inhibit several cytochrome P450 and UDP-glucuronosyltransferase (UGT) enzymes involved in drug metabolism, including CYP2C8, CYP2C9, UGT1A9, UGT2B4 and UGT2B7. Bovine serum albumin (BSA) enhances these P450 and UGT activities by sequestering fatty acids that are released during the course of incubations, especially with human liver microsomes (HLM) as the enzyme source. Here we report the effects of BSA on CYP1A2-catalyzed phenacetin (PHEN) O-deethylation and lidocaine (LID) N-deethylation using HLM and E.coli-expressed CYP1A2 as the enzyme sources. BSA (2% w/v) reduced (p < 0.05) the K(m) values of the high affinity components of human liver microsomal PHEN and LID deethylation by approximately 70%, without affecting V(max). The K(m) values for PHEN and LID deethylation by E.coli-expressed CYP1A2 were reduced to a similar extent. A fatty acid mixture, comprising 3 μM each of oleic acid and linoleic acid and 1.5 μM arachidonic acid, doubled the K(m) value for PHEN O-deethylation by recombinant CYP1A2. Inhibition was reversed by the addition of BSA. K(i) values for the individual fatty acids ranged from 4.7 μM to 16.7 μM. Single point in vitro - in vivo extrapolation (IV-IVE) based on the human liver microsomal kinetic parameters obtained in the presence, but not absence, of BSA predicted in vivo hepatic clearances of PHEN O-deethylation and LID N-deethylation that were comparable to values reported in humans, although in vivo intrinsic clearances were underpredicted. Prediction of the in vivo clearances of the CYP1A2 substrates observed here represents an improvement on other experimental systems employed for IV-IVE.
Nitsupa Wattanachai; Wichittra Tassaneeyakul; Andrew Rowland; David J Elliot; Kushari Bowlagaha; Kathleen M Knights; John O Miners
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-2-13
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  -     ISSN:  1521-009X     ISO Abbreviation:  -     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-2-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
1 Khon Kaen University;
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