Differential salivary disposition of linezolid and its two major metabolites (PNU-142300 and PNU-142586) after a single dose in healthy adults

BACKGROUND: Salivary therapeutic drug monitoring of linezolid has been proposed as a non-invasive alternative to blood sampling for pharmacokinetic assessment. However, the salivary disposition and pharmacokinetics of the two major linezolid metabolites, PNU-142300 and PNU-142586, have not been characterized. OBJECTIVE: To evaluate the salivary disposition and serum protein binding of PNU-142300 and PNU-142586 using pharmacokinetic analysis. METHODS: In this exploratory study, six healthy adult volunteers received a single intravenous dose of linezolid. Serial blood and saliva samples were collected for 10 h after dosing. The total and protein-unbound concentrations of linezolid and its two major metabolites, PNU-142300 and PNU-142586, were quantified using validated high-performance liquid chromatography methods. RESULTS: Linezolid was consistently quantifiable in saliva, and its salivary concentration-time profile closely followed that of protein-unbound serum exposure. PNU-142300 and PNU-142586 were readily quantifiable in blood but remained below the lower limit of quantification in saliva in all participants at all sampling time points. CONCLUSIONS: Under the conditions studied, linezolid was quantifiable in saliva, whereas its two major metabolites were not, indicating different salivary disposition profiles for the parent drug and its metabolites. Salivary concentrations were consistent with protein-unbound serum exposure to linezolid under the conditions studied, whereas exposure to PNU-142300 and PNU-142586 could not be assessed using saliva and required blood-based measurements in the present study.