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 < or =4 microg/ml and in vivo doses < or =10 mg/kg. Because linezolid also competitively inhibits human monoamine oxidase-A (MAO-A; Ki = 55 microM), we monitored its effects on the cardiovascular responses to tyramine and amine cold remedies in comparison with standard MAO inhibitors. In anesthetized rats, the pressor response to 16 microg i.v. tyramine was potentiated by the MAO-A inhibitors 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. tyramine independent of changes in alpha-adrenoceptor reactivity, but this effect was not enhanced chronically (90-100 mg/kg/day). In conscious rats, 30 mg/kg/day oral linezolid (8 microg/ml plasma concentration) minimally affected the pressor response to 20 mg/kg oral tyramine, whereas 100 mg/kg/day linezolid (20 microg/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, phenylpropanolamine, and dextromethorphan interactions. These studies demonstrate that high-dose linezolid only moderately potentiates the cardiovascular effects of tyramine and validate these models for evaluating such MAO inhibitory interactions.
Humphrey
S J
SJ
Pharmacology and Drug Metabolism Research, Pharmacia Corporation, Kalamazoo, Michigan 49007-4940, USA. humphrey@pharmacia.com
Curry
J T
JT
Turman
C N
CN
Stryd
R P
RP
D000081:Acetamides / Q000008:administration & dosage* / Q000737:chemistry; D000284:Administration, Oral; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000737:chemistry; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D000069349:Linezolid; D008297:Male; D008995:Monoamine Oxidase / Q000187:drug effects; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D023303:Oxazolidinones / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013566:Sympathomimetics / Q000494:pharmacology*; D014439:Tyramine / Q000494:pharmacology*
D000081:Acetamides; D000890:Anti-Infective Agents; D008996:Monoamine Oxidase Inhibitors; D023303:Oxazolidinones; D013566:Sympathomimetics; D008995:Monoamine Oxidase; D000069349:Linezolid; D014439:Tyramine