Metabolism of Daptomycin
Daptomycin undergoes minimal to no hepatic metabolism and is excreted primarily unchanged by the kidneys, with approximately 52% of the administered dose recovered in urine as microbiologically active drug and only minor inactive oxidative metabolites detected. 1
Metabolic Pathway
Daptomycin is not metabolized by human liver microsomes in vitro studies, indicating negligible hepatic cytochrome P450 involvement 1
No metabolites are observed in plasma following administration of daptomycin 6 mg/kg to adult subjects on Day 1 of therapy 1
Minor amounts of three oxidative metabolites and one unidentified compound are detected only in urine, not in plasma, suggesting limited peripheral metabolism 1
The specific site of metabolism has not been identified, though it appears to occur outside the liver 1
Excretion and Elimination
Approximately 78% of the administered dose is recovered in urine based on total radioactivity (52% as microbiologically active drug), while only 5.7% is recovered in feces over 9 days 1
Renal excretion is the primary route of elimination, making daptomycin particularly susceptible to accumulation in patients with renal impairment 1, 2
The elimination half-life is approximately 9 hours in patients with normal renal function (creatinine clearance >80 mL/min), but increases to 14.7 hours in moderate renal impairment and further in severe renal dysfunction 1
Clinical Implications
Protein binding is 90-93% to serum albumin in a concentration-independent manner, which limits distribution (volume of distribution ~0.1 L/kg) 1, 2
Dosage adjustment is required for creatinine clearance <30 mL/min, as renal clearance decreases by 46% in severe renal impairment, leading to 2-3 fold higher AUC compared to normal renal function 1
Hepatic impairment does not affect daptomycin pharmacokinetics, as protein binding and clearance remain similar in patients with Child-Pugh Class B hepatic impairment compared to healthy subjects 1