Cytochrome P450-dependent metabolism of midazolam in hepatic microsomes from chickens, turkeys, pheasant and bobwhite quail.
In vitro putative cytochrome P450 3A mediated activity, and inhibition thereof, were measured in four avian species using midazolam (MDZ) as a substrate and ketoconazole as an inhibitor. All species produced 1-hydroxymidazolam (1-OH MDZ) to a much greater extent than 4-hydroxymidazolam (4-OH MDZ). Calculated Vmaxapparent values for formation of 1-OH MDZ were 117+/-17, 239+/-108, 437+/-168, and 201+/-55 pmol/mg protein*min and Kmapparent values were 2.1+/-0.8, 2.4+/-1.6, 6.7+/-5.1 and 3.2+/-2.1 microm for chicken, turkey, pheasant and bobwhite quail, respectively. For the formation of 4-OH MDZ the Vmaxapparent values were 21+/-10, 94+/-46, 144+/-112, and 68+/-30 pmol/mg protein*min and Kmapparent values for 4-OH MDZ formation were 12.4+/-10.1, 18.0+/-10.8, 38.6+/-34.7 and 29.1+/-10.1 microm for chicken, turkey, pheasant and bobwhite quail, respectively. In all four species, ketoconazole inhibited the production of both major metabolites of MDZ, with 4-OH MDZ formation more sensitive to inhibition than 1-OH MDZ. Pheasant and bobwhite quail appeared most sensitive to ketoconazole inhibition.
Cortright
K A
KA
Department of Environmental Toxicology, University of California, Davis, CA 95616, USA. kacortright@ucdavis.edu
Craigmill
A L
AL
D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000494:pharmacology*; D001717:Birds / Q000378:metabolism*; D002645:Chickens / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D007654:Ketoconazole / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism; D008874:Midazolam / Q000378:metabolism / Q000493:pharmacokinetics*; D011784:Quail / Q000378:metabolism; D013045:Species Specificity; D014422:Turkeys / Q000378:metabolism
D014151:Anti-Anxiety Agents; D000935:Antifungal Agents; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D007654:Ketoconazole