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Gender difference CYP2C8 metabolism

Albert P Li, Kari E Schlicht
A higher throughput platform was developed for the determination of K(M) values for isoformselective P450 substrates in human hepatocytes via incubation of the hepatocytes with substrates in 384- well plates and metabolite quantification by RapidFire™ mass spectrometry. Isoform-selective P450 substrates were incubated at 8 concentrations in triplicate with cryopreserved human hepatocytes from 16 donors. The metabolic pathways examined were the CYP1A2-catalyzed tacrine 1-hydroxylation, CYP2B6-catalyzed bupropion hydroxylation, CYP2C8-catalyzed amodiaquine N-deethylation, CYP2C9- catalyzed diclofenac 4'-hydroxylation, CYP2D6-catalyzed dextromethorphan O-demethylation, and CYP3A4-catalyzed midazolam 1'-hydroxylation...
2014: Drug Metabolism Letters
Paulo Arnaldo, Ricardo Estevão Thompson, Márcia Quinhones Lopes, Philip Noel Suffys, Adalberto Rezende Santos
BACKGROUND: The cytochrome P450 enzymes (CYP) play an important role in the metabolism of many therapeutic agents. The activities of different enzymes exhibit variability in different populations, which causes variations in drug response or toxicity. The CYP2B6 and CYP2C8 enzymes are encoded by polymorphic genes characterised by different single nucleotide polymorphisms (SNPs). Several of these CYP variants are often associated with slow metabolism phenotypes. This study aimed to analyse the frequencies of allelic variants of CYP2B6 and CYP2C8 in the Mozambican population...
July 2013: Malaysian Journal of Medical Sciences: MJMS
Yan-Ling He
Vildagliptin is an orally active, potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor, shown to be effective and well tolerated in patients with type 2 diabetes mellitus (T2DM) as either monotherapy or in combination with other anti-diabetic agents. Vildagliptin possesses several desirable pharmacokinetic properties that contribute to its lower variability and low potential for drug interaction. Following oral administration, vildagliptin is rapidly and well absorbed with an absolute bioavailability of 85%...
March 1, 2012: Clinical Pharmacokinetics
Orianne Videau, Sylvain Pitarque, Sylvie Troncale, Patrick Hery, Etienne Thévenot, Marcel Delaforge, Henri Bénech
We recently designed the CIME cocktail consisting of 10 drugs to assess the activity of the major human CYPs (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A), a phase II enzyme (UGT1A1/6/9), two drug transporters (P-gp and OATP1B1) and a component of the renal function ( Videau et al. 2010 ). The present work aimed at studying the usefulness of the CIME cocktail in the rat.The CIME cocktail was given per os to three male and three female rats, or incubated with rat liver microsomes. Parent substrates and metabolites were quantified by LC-MS/MS in plasma, urine and hepatic microsomal media, and phenotyping index were subsequently calculated...
April 2012: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Mette T Skaanild, Christian Friis
The cytochrome P450 2C (CYP2C) subfamily in human beings includes four different isoenzymes that metabolize different substrates although with some cross reactivity. Some of these substrates (e.g. diclofenac and tolbutamide), have been investigated in porcine microsomes, but without identifying the specific CYP catalysing the reactions. The objective of this study was therefore to test some CYP2C substrates and identify the porcine CYP2C responsible for the reaction. Three substrates, paclitaxel, tolbutamide and omeprazole, were chosen, as they are metabolized by three different CYP2C isoenzymes in human beings...
November 2008: Basic & Clinical Pharmacology & Toxicology
Gregory S Gorman, Lori Coward, Corenna Kerstner-Wood, Lea Cork, Izet M Kapetanovic, Wayne J Brouillette, Donald D Muccio
The present study was conducted to compare the in vitro phase I and phase II metabolic profiles of (2E,4E,6Z,8E)-8-(3',4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid (9cUAB30) in human, rat, and dog microsomes and to characterize and identify the associated metabolic kinetics and specific isozymes from human liver microsomes (HLM) responsible for metabolism, respectively. Data from these experiments revealed that nine (M1-M9) phase I metabolites along with a single glucuronide conjugate were observed across the species investigated...
July 2007: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Lorraine M King, James V Gainer, Gloria L David, Ding Dai, Joyce A Goldstein, Nancy J Brown, Darryl C Zeldin
CYP2J2 and CYP2C8 metabolize arachidonic acid (AA) to cis-epoxyeicosatrienoic acids (EETs), which play a central role in regulating renal tubular fluid-electrolyte transport and vascular tone. We hypothesized that functionally relevant polymorphisms in the CYP2J2 or CYP2C8 genes influence hypertension risk. We examined associations between CYP2J2*7 (G-50 T promoter) and CYP2C8*3 (Arg139Lys and Lys399Arg, which are in 100% linkage disequilibrium) polymorphisms and hypertension in a biethnic population from Tennessee...
January 2005: Pharmacogenetics and Genomics
Andrew Parkinson, Daniel R Mudra, Cory Johnson, Anne Dwyer, Kathleen M Carroll
We have measured cytochrome P450 (CYP) activity in nearly 150 samples of human liver microsomes and 64 samples of cryopreserved human hepatocytes, and we have performed induction studies in over 90 preparations of cultured human hepatocytes. We have analyzed these data to examine whether the expression of CYP enzyme activity in liver microsomes and isolated hepatocytes or the inducibility of CYP enzymes in cultured hepatocytes is influenced by the gender, age, or ethnicity of the donor (the latter being limited to Caucasians, African Americans, and Hispanics due to a paucity of livers from Asian donors)...
September 15, 2004: Toxicology and Applied Pharmacology
M Beconi, A Mao, M Creighton, C E C A Hop, S H L Chiu, R Eydelloth, R Franklin, F Tang, N Yu, S Vincent
1. The metabolism of a substituted 2,4-thiazolidinedione (P1) with dual PPARalpha/gamma activity was evaluated in male and female rats, dogs and monkeys. A para-hydroxylated metabolite (M1) with potent PPARgamma-selective agonist, was a major circulating drug-related component in female rats, dogs and monkeys, but not in male rats (M1-to-P1 exposure ratio of <1, 3-5, 5 and 5-11 in male rat, monkey, female rat, and dog, respectively). 2. M1 (%) formed in vitro (5, 53, 57-65, 67 and 67% in male rat, monkey, female rat, dog, and human liver microsomes, respectively), rank ordered with M1 (%) formed in vivo (24-45, 53-57, 78, 75-85%, for male rat, monkey, female rat and dog, respectively, after oral administration of P1)...
July 2003: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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