Combined effect of propranolol with nifedipine or with diltiazem on rat liver monooxygenase activities.
The effects of two Ca2+ antagonists nifedipine (NF) and diltiazem (DL) and of the nonselective beta-adrenergic blocking agent propranolol (PR) on the hexobarbital (HB) sleeping time and on the activity of some liver drug-metabolizing enzyme systems in male Wistar rats were studied. Two h after single oral administration PR (50 mg/kg) did not change HB sleeping time, while NF (50 mg/kg) and DL (30 mg/kg) prolonged it by 171.2 and 99.6%, respectively. Coadmistration of PR with DL or with NF significantly prolonged HB sleep by 240.7 and 129%, respectively. Only NF increased aniline 4-hidroxylase (AH) activity (by 92%) and the total P-450 content (by 24%). PR and NF increased cytochrome b5 content and this effect was also observed with the combinations PR + NF (by 109%) and PR + DL (by 102%). The NADPH cytochrome P-450 reductase activity was significantly decreased by NF and DL and after their combination with PR. The ethymorphine-N-demethylase (EMND) and amidopyrine-N-demethylase (APND) activities were not changed. The effects of PR, NF and DL administrated alone or in combination on liver oxidative metabolism are considered as possible mechanisms of drug interactions.
Koleva
M
M
Laboratory of Drug Toxicology, Institute of Physiology, Bulgarian Academy of Sciences, Sofia. mrkoleva@iph.bio.bas.bg
Kastelova
A
A
Staneva-Stoytcheva
D
D
Stoytchev
T
T
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000633:Aminopyrine N-Demethylase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D015786:Cytochromes b5 / Q000187:drug effects / Q000378:metabolism; D004110:Diltiazem / Q000494:pharmacology; D005037:Ethylmorphine-N-Demethylase / Q000187:drug effects / Q000378:metabolism; D006591:Hexobarbital / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009251:NADPH-Ferrihemoprotein Reductase / Q000187:drug effects / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012890:Sleep / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D006993:Hypnotics and Sedatives; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D011433:Propranolol; D006591:Hexobarbital; D000633:Aminopyrine N-Demethylase; D005037:Ethylmorphine-N-Demethylase; D009251:NADPH-Ferrihemoprotein Reductase; D004110:Diltiazem; D009543:Nifedipine