Can a cocktail designed for phenotyping pharmacokinetics and metabolism enzymes in human be used efficiently in rat?
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.The CIME cocktail could therefore be used in the rat to phenotype rapidly and simultaneously CYP3A1/2 with omeprazole/omeprazole-sulfone, midazolam/1'-hydroxymidazolam or 4-hydroxymidazolam and/or dextromethorphan/3-methoxymorphinan, CYP2C6/11 with tolbutamide/4-hydroxytolbutamide, CYP2D1/2 with omeprazole/5-hydroxyomeprazole or dextromethorphan/dextrorphan, and UGT1A6/7 with acetaminophen/acetaminophen-glucuronide. Our results confirmed also several known gender differences and brought new information on the urinary excretion of rosuvastatin. However, the major rat CYPs, CYP2C11 and CYP2C12, are not specifically assessed. An optimized version of the CIME cocktail should therefore be designed and would be of major importance to more largely phenotype DMPK enzymes in rats to study DMPK variability factors such as disease, age, or to exposure to inductors or inhibitors.
CEA, DSV/iBiTecS/Pharmacology and Immunoanalysis Unit, CEA/Saclay, Gif-Sur-Yvette cedex, France.
Orianne
O
Videau
Sylvain
S
Pitarque
Sylvie
S
Troncale
Patrick
P
Hery
Etienne
E
Thévenot
Marcel
M
Delaforge
Henri
H
Bénech
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D010599:Pharmacokinetics; D010641:Phenotype; D051381:Rats; D012737:Sex Factors; D013045:Species Specificity; D053719:Tandem Mass Spectrometry
D026901:Membrane Transport Proteins; D003577:Cytochrome P-450 Enzyme System