Tags

Type your tag names separated by a space and hit enter

Oxidative metabolism of monensin in rat liver microsomes and interactions with tiamulin and other chemotherapeutic agents: evidence for the involvement of cytochrome P-450 3A subfamily.
Drug Metab Dispos. 1999 Sep; 27(9):1039-44.DM

Abstract

Monensin (MON) is an ionophore antibiotic widely used in veterinary practice as a coccidiostatic or a growth promoter. The aims of this study were to characterize the P-450 isoenzyme(s) involved in the biotransformation of the ionophore and to investigate how this process may be affected by tiamulin and other chemotherapeutic agents known to produce toxic interactions with MON when administered concurrently in vivo. In liver microsomes from untreated rats (UT) or from rats pretreated, respectively, with ethanol (ETOH), beta-naphthoflavone (betaNAF), phenobarbital (PB), pregnenolone 16alpha-carbonitrile (PCN), or dexamethasone (DEX), the rate of MON O-demethylation was the following: DEX > PCN > PB >> UT = ETOH > betaNAF; similar results were obtained by measuring total MON metabolism. In addition, the extent of triacetyloleandomycin-mediated P-450 complexes was greatly reduced by the prior addition of 100 microM MON. In DEX-treated microsomes, MON O-demethylation was found to fit monophasic Michaelis-Menten kinetics (K(M) = 67.6 +/- 0.01 microM; V(max) = 4.75 +/- 0.76 nmol/min/mg protein). Tiamulin markedly inhibited this activity in an apparent competitive manner, with a calculated K(i) (Dixon plot) of 8.2 microM and an IC(50) of about 25 microM. At the latter concentration, only ketoconazole or metyrapone, which can bind P-450 3A, inhibited MON O-demethylase to a greater extent than tiamulin, whereas alpha-naphthoflavone, chloramphenicol, or sulphametasine was less effective. These results suggest that P-450 3A plays an important role in the oxidative metabolism of MON and that compounds capable of binding or inhibiting this isoenzyme could be expected to give rise to toxic interactions with the ionophore.

Authors+Show Affiliations

Department of Animal Pathology, Division of Pharmacology and Toxicology, University of Turin, Italy. cnebbia@veter.unito.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10460804

Citation

Nebbia, C, et al. "Oxidative Metabolism of Monensin in Rat Liver Microsomes and Interactions With Tiamulin and Other Chemotherapeutic Agents: Evidence for the Involvement of Cytochrome P-450 3A Subfamily." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 27, no. 9, 1999, pp. 1039-44.
Nebbia C, Ceppa L, Dacasto M, et al. Oxidative metabolism of monensin in rat liver microsomes and interactions with tiamulin and other chemotherapeutic agents: evidence for the involvement of cytochrome P-450 3A subfamily. Drug Metab Dispos. 1999;27(9):1039-44.
Nebbia, C., Ceppa, L., Dacasto, M., Carletti, M., & Nachtmann, C. (1999). Oxidative metabolism of monensin in rat liver microsomes and interactions with tiamulin and other chemotherapeutic agents: evidence for the involvement of cytochrome P-450 3A subfamily. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 27(9), 1039-44.
Nebbia C, et al. Oxidative Metabolism of Monensin in Rat Liver Microsomes and Interactions With Tiamulin and Other Chemotherapeutic Agents: Evidence for the Involvement of Cytochrome P-450 3A Subfamily. Drug Metab Dispos. 1999;27(9):1039-44. PubMed PMID: 10460804.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oxidative metabolism of monensin in rat liver microsomes and interactions with tiamulin and other chemotherapeutic agents: evidence for the involvement of cytochrome P-450 3A subfamily. AU - Nebbia,C, AU - Ceppa,L, AU - Dacasto,M, AU - Carletti,M, AU - Nachtmann,C, PY - 1999/8/26/pubmed PY - 1999/8/26/medline PY - 1999/8/26/entrez SP - 1039 EP - 44 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 27 IS - 9 N2 - Monensin (MON) is an ionophore antibiotic widely used in veterinary practice as a coccidiostatic or a growth promoter. The aims of this study were to characterize the P-450 isoenzyme(s) involved in the biotransformation of the ionophore and to investigate how this process may be affected by tiamulin and other chemotherapeutic agents known to produce toxic interactions with MON when administered concurrently in vivo. In liver microsomes from untreated rats (UT) or from rats pretreated, respectively, with ethanol (ETOH), beta-naphthoflavone (betaNAF), phenobarbital (PB), pregnenolone 16alpha-carbonitrile (PCN), or dexamethasone (DEX), the rate of MON O-demethylation was the following: DEX > PCN > PB >> UT = ETOH > betaNAF; similar results were obtained by measuring total MON metabolism. In addition, the extent of triacetyloleandomycin-mediated P-450 complexes was greatly reduced by the prior addition of 100 microM MON. In DEX-treated microsomes, MON O-demethylation was found to fit monophasic Michaelis-Menten kinetics (K(M) = 67.6 +/- 0.01 microM; V(max) = 4.75 +/- 0.76 nmol/min/mg protein). Tiamulin markedly inhibited this activity in an apparent competitive manner, with a calculated K(i) (Dixon plot) of 8.2 microM and an IC(50) of about 25 microM. At the latter concentration, only ketoconazole or metyrapone, which can bind P-450 3A, inhibited MON O-demethylase to a greater extent than tiamulin, whereas alpha-naphthoflavone, chloramphenicol, or sulphametasine was less effective. These results suggest that P-450 3A plays an important role in the oxidative metabolism of MON and that compounds capable of binding or inhibiting this isoenzyme could be expected to give rise to toxic interactions with the ionophore. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/10460804/Oxidative_metabolism_of_monensin_in_rat_liver_microsomes_and_interactions_with_tiamulin_and_other_chemotherapeutic_agents:_evidence_for_the_involvement_of_cytochrome_P_450_3A_subfamily_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10460804 DB - PRIME DP - Unbound Medicine ER -