Doripenem

Doripenem is a broad-spectrum carbapenem class of antibacterial with activity against aerobic and anaerobic Gram-positive and Gram-negative bacteria.Doripenem exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis. Doripenem inactivates multiple essential penicillin-binding proteins (PBPs) resulting in inhibition of cell wall synthesis with subsequent cell death. In E. coli and P. aeruginosa,Doripenem binds to PBP 2, which involved in the maintenance of cell shape, as well as to PBPs 3 and 4.Absorption: Mean plasma concentrations of Doripenem following a single 1-hour intravenous infusion of a 500 mg dose to 24 healthy subjects is 23.0 (6.6) pg/mL. The pharmacokinetics of Doripenem (Cmax and AUC) are linear over a dose range of 500 mg to 1 g when intravenously infused over 1 hour. There is no accumulation of Doripenem following multiple intravenous infusions of either 500 mg or 1 g administered every 8 hours for 7 to 10 days in subjects with normal renal function.Distribution: The average binding of Doripenem to plasma proteins is approximately 8.1% and is independent of plasma drug concentrations. The median (range) volume of distribution at steady state in healthy subjects is 16.8 L (8.09-55.5 L), similar to extracellular fluid volume (18.2 L).Metabolism: Metabolism of doripenem to a microbiologically inactive ring-opened metabolite (doripenem-M1) occurs primarily via dehydropeptidase-l. In pooled human liver microsomes, no in vitro metabolism of Doripenem could be detected, indicating that Doripenem is not a substrate for hepatic CYP450 enzymes.Excretion: Doripenem is primarily eliminated unchanged by the kidneys. The mean plasma terminal elimination half-life of Doripenem in healthy non-elderly adults is approximately 1 hour and mean (SD) plasma clearance is 15.9 (5.3) L/hour. Mean renal clearance is 10.8 (3.5) L/hour. In healthy adults given a single 500 mg dose a mean of 70% and 15% of the dose was recovered in urine as unchanged drug and the ring-opened metabolite, respectively, within 48 hours.