Effects of multiple doses of moricizine hydrochloride on its pharmacokinetics and hepatic microsomal enzymes in rats.
We studied the influence of chronic moricizine hydrochloride (MRZ) treatment on the drug's pharmacokinetics and on drug metabolizing enzyme activities in rats. Separate groups of 8 rats (4 males and 4 females) were treated with 40 and 100 mg/kg oral MRZ once daily for 7 days and saline control for 7 days prior to the preparation of hepatic microsomal enzyme suspensions. Depending on the substrate, treatments with multiple oral MRZ increased or decreased hepatic microsomal enzyme activities. For the pharmacokinetic study, rats (4 males and 4 females) were treated with 40 mg/kg oral MRZ once daily for 7 days. A comparison of MRZ pharmacokinetics obtained on day 1 relative to day 7 revealed that both AUC0-t and AUC0-infinity increased about 7-fold in males and 2-fold in females. Cmax also increased about 5-fold from day 1 to day 7 in males. These increases in blood concentrations and AUC's are likely due to enzyme inhibition. Results obtained from female rats on days 1, 4 and 7 suggest that metabolic changes probably occur after the 4th day of dosing. Therefore, chronic MRZ treatment affected its pharmacokinetics and hepatic metabolizing enzyme activities in rats.
King
S Y
SY
Drug Metabolism and Pharmacokinetics Section, Du Pont Merck Pharmaceutical Company, Newark, DE 19714.
Powel
R J
RJ
Wong
Y N
YN
Davidson
A F
AF
Vincent
D R
DR
Quon
C Y
CY
Pieniaszek
H J
HJ
D000284:Administration, Oral; D000818:Animals; D004334:Drug Administration Schedule; D005260:Female; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D016293:Moricizine / Q000031:analogs & derivatives / Q000032:analysis / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012737:Sex Factors
D016293:Moricizine; C076194:moricizine sulfoxide