Cardiovascular sympathomimetic amine interactions in rats treated with monoamine oxidase inhibitors and the novel oxazolidinone antibiotic linezolid

Linezolid (PNU-100766) is a new gram-positive oxazolidinone antibiotic that is effective at in vitro concentrations less than or equal to4 mug/ml and in vivo doses less than or equal to 10 mg/kg. Because linezolid also compet itively inhibits human monoamine oxidase-A (MAO-A; K-i = 55 muM), we monito red its effects on the cardiovascular responses to tyramine and amine cold remedies in comparison with standard MAO inhibitors. In anesthetized rats, the presser response to 16 mug i.v. tyramine was potentiated by the MAO-A i nhibitors clorgyline (0.1-1.0 mg/kg i.v.) and moclobemide (5.0-50 mg/kg p.o .), but not by the MAO-B inhibitor selegiline (0.15-15 mg/kg p.o.). Fifteen milligrams per kilogram intravenous linezolid weakly potentiated i.v. tyra mine independent of changes in alpha -adrenoceptor reactivity, but this eff ect was not enhanced chronically (90-100 mg/kg/day). In conscious rats, 30 mg/kg/day oral linezolid (8 mug/ml plasma concentration) minimally affected the presser response to 20 mg/kg oral tyramine, whereas 100 mg/kg/day line zolid (20 mug/ml plasma concentration) moderately potentiated this response similar to 3 mg/kg per day moclobemide. Linezolid's tyramine potentiation was reversible, attenuated by food, and independent of pseudoephedrine, phe nylpropanolamine, and dextromethorphan interactions. These studies demonstr ate that high-dose linezolid only moderately potentiates the cardiovascular effects of tyramine and validate these models for evaluating such MAO inhi bitory interactions.