Modulation of cytochrome P450 metabolism by ergonovine and dihydroergotamine.
This study investigated modulation of the cytochrome P450 3A (CYP3A4)-mediated metabolism of ergotamine (ET) by ergonovine and dihydroergotamine. Liver microsomes were prepared from rats treated i.p. for 4 d with: low (10 mM) or high (100 mM) levels of dexamethasone (DM10 and DM100), dihydroergotamine, ergonovine, or control. Cytochrome P450 activity was evaluated using ET and its isomers as substrate. Ergotamine was converted to its metabolites at rates of 0.385 or 0.535 (SE = 0.040) nM/microg protein/min when incubated with liver microsomes from DM10 or DM100 treated rats, respectively. These rates were higher than for rats on other treatments. Induction of CYP34A activity was not greater for ergonovine or dihydroergotamine treatments than for controls. Both ergonovine and dihydroergotamine treatments inhibited in vitro CYP3A4 activity in a dose dependent manner producing quadratic inhibition curves.
Moubarak
A S
AS
Department of Animal Sciences, University of Arkansas, Fayetteville, AR 72701, USA.
Rosenkrans
C F
CF
Johnson
Z B
ZB
D000818:Animals; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004087:Dihydroergotamine / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004874:Ergonovine / Q000008:administration & dosage / Q000494:pharmacology*; D004876:Ergot Alkaloids / Q000008:administration & dosage / Q000494:pharmacology*; D007263:Infusions, Parenteral; D007536:Isomerism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004876:Ergot Alkaloids; D004087:Dihydroergotamine; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D004874:Ergonovine