Changes in rat liver monooxygenase activities after administration of atenolol, nifedipine and diltiazem alone and in combination.
The effects of the Ca2+ antagonists nifedipine (NF) and diltiazem (DL) and of the cardioselective beta 1-adrenergic blocking agent atenolol (AT) on the hexobarbital (HB) sleeping time and on the activity of some liver drug-metabolizing enzyme systems in male Wistar rats were studied. Two hours after single oral administration, atenolol (150 mg/kg) did not change hexobarbital sleeping time, while nifedipine (50 mg/kg) and diltiazem (30 mg/kg) prolonged it by 171.2 and 99.6%, respectively. Coadministration of atenolol with diltiazem or with nifedipine significantly prolonged hexobarbital sleep by 205 and 283%, respectively. Administered alone, atenolol decreased the ethylmorphine-N-demethylase (EMND) activity, but the amidopyrine-N-demethylase (APND) activity was not changed in any of the treated groups. Atenolol and nifedipine significantly increased aniline-4-hydroxylase (AH) activity and this effect was also observed with the combinations AT + NF and AT + DL. The NADPH cytochrome P-450 reductase activity was significantly decreased by nifedipine and diltiazem. Only nifedipine increased the total content of cytochrome P-450 (by 23.8%). Atenolol and diltiazem tended to increase the content of cytochrome b5 which was increased by nifedipine by 97.6%. The same effect was observed with the combinations AT + NF and AT + DL. The results suggest that NF, AT + NF and AT + DL produced the manifested changes in hepatic oxidative metabolism. The decreased EMND activity by atenolol, however, and the prolongation of hexobarbital sleeping time by nifedipine, diltiazem and their coadministration with atenolol did not correlate with enhanced microsomal P-450 and b5 content.
Laboratory of Drug Toxicology, Institute of Physiology, Bulgarian Academy of Sciences, Sofia, Bulgaria. antonia@iph.bio.bas.bg
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Kastelova
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M
Koleva
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Staneva-Stoytcheva
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000633:Aminopyrine N-Demethylase / Q000187:drug effects / Q000378:metabolism; D000815:Aniline Hydroxylase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001262:Atenolol / Q000008:administration & dosage / Q000494:pharmacology; 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; D004359:Drug Therapy, Combination; 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; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009251:NADPH-Ferrihemoprotein Reductase / Q000187:drug effects / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D010088:Oxidoreductases / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D006993:Hypnotics and Sedatives; D001262:Atenolol; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D006591:Hexobarbital; D010088:Oxidoreductases; D000815:Aniline Hydroxylase; D000633:Aminopyrine N-Demethylase; D005037:Ethylmorphine-N-Demethylase; C019666:amidopyrine N-demethylase; D009251:NADPH-Ferrihemoprotein Reductase; D004110:Diltiazem; D009543:Nifedipine