Pharmacokinetics, toxicokinetics, distribution, metabolism and excretion of linezolid in mouse, rat and dog

摘要: 1. Linezolid (ZYVOX), the first of a new class antibiotics, oxazolidinones, is approved for treatment Gram-positive bacterial infections. 2. The aim was to determine absorption, distribution, metabolism and excretion (ADME) linezolid in mouse, rat dog support preclinical safety studies clinical development. 3. Conventional replicate study designs were employed animal experiments, biofluids assayed by HPLC or HPLC-MS. 4. rapidly absorbed after p.o. dosing with an bioavailability > 95% dog, 70% mouse. Twenty-eight-day i.v./p.o. toxicokinetic (20-200mg kg(-1) day(-1)) (10-80 mg revealed neither meaningful increase clearance nor accumulation upon multiple dosing. 5. had limited protein binding (<35%) very well distributed most extravascular sites, volume distribution at steady-state (V(ss)) approximately equal total body water. 6. circulated mainly as parent drug excreted two inactive carboxylic acids, PNU-142586 PNU-142300. Minor secondary metabolites also characterized. In all species, rate determined metabolism. 7. Radioactivity recovery essentially complete within 24-48 h. Renal major elimination route. Parent underwent renal tubular reabsorption, significantly slowing allowing slow metabolic process become rate-limiting overall clearance. 8. It concluded that ADME data relatively consistent across species supported principal non-clinical species.