Imipenem pharmacokinetics

Imipenem-cilastatin is only available for intramuscular or intravenous administration because oral bioavailability is poor. The enzyme, dehydropeptidase 1, present in renal tubules, converts imipenem to an inactive metabolite. To decrease metabolic clearance, imipenem is combined with cilastatin, an inhibitor of dehydropeptidase I. Additional pharmacokinetic information appears in Table 45.2. 

Mechanism of Action A fixed-combination carbapenem. Imipenem penetrates the bacterial cell membrane and binds to penicillin-binding proteins, inhibiting cell wall synthesis. Cilastatin competitively inhibits the enzyme dehydropeptidase, preventing renal metabolism of imipenem. Therapeutic Effect Produces bacterial cell death. Pharmacokinetics Readily absorbed after IM administration. Protein binding 13%-21%. Widely distributed. Metabolized in the kidneys. Primarilyexcreted in urine. Removed by hemodialysis. Half-life 1 hr (increased in impaired renal function). 

Pharmacokinetic studies have not been performed in horses however, i.v. doses of 0.7-1.Img/kg three times a day have been suggested as being suitable for use in small animals. Imipenem has to be administered i.v. because it is not absorbed following p.o. administration. Imipenem has been shown to penetrate inflamed meninges. It is metabolized extensively by the renal tubules to a potentially toxic compound. Therefore, it is usually combined with cilastatin, a drug that inhibits the renal tubular enzymes. The combined product produces high urine concentrations of active antibiotic and avoids renal toxicity. In the presence of cilastatin, 70% of a dose of imipenem is excreted unchanged in the urine. The half-life of imipenem in the dog is 30-45 nrin. 

Mueller BA, Scarim SK, Macias WL. Comparison of imipenem pharmacokinetics in patients with acute or chronic renal failure treated with continuous hemofiltration. Am J Kidney Dis 1993 21 172-179. 

Tegeder I, Bremer F, Oelkers R, et al. Pharmacokinetics of imipenem-cilastatin in critically ill patients undergoing continuous venovenous hemofiltration. Antimicrob Agents Chemother 1997 41 2640-2645. 

The combination of imipenem and cilastatin overcame the pharmacokinetic [184], metabolic and toxicological chaUenges presented by this powerful antibiotic. 

Verpooten GA, Verbist L, Buntinx AP, Entwistle LA, Jones KEI, De Broe ME. The pharmacokinetics of imipenem (thienamycin-formamidin) and the renal dehydropeptidase inhibitor cilastatin sodium in normal subjects and patients with renal failure. Brit J Clin Pharmacol 1984 18 193-193. 

Paradis, D. Vall4e, F. Allard, S. Bisson, C. Daviau, N. Drapeau, C. Auger, F. LeBel, M. Comparative study of pharmacokinetics and serum bactericidal activities of cefpirome, ceftazidime, ceftriaxone, imipenem, and ciprofloxacin. Aretimicro6.Agerafs Chemother., 1992, 36, 2085-2092... 

Adamis G, Papaioannou MG, Giamarellos-Bourboulis EJ, Gargalianos P, Kosmidis J, Gia-marellouH, Pharmacokinetic interactions of ceftazidime, imipenem andaztreonam witii amikacin in healthy volunteers, IntJAntimicrob Agents (2004) 23,144-9,... 

Fig. 5.32). The pharmacokinetics of meropenem closely resemble that of the imipenem/cUastatin combination, and its nephro-and neuro-toxicity is correspondingly low. 

Carbapenems An old Chinese man with epilepsy had seizures when meropenem was added to treatment with valproate [407 ]. In a retrospective study of six critically ill patients taking valproate who concurrently received meropenem (n = 4), imipenem (n = 1), or ertapenem (n = 1) mean plasma valproate trough concentrations fell by 58% and estimated mean valproate clearance increased by 191% compared with values obtained while they were not receiving a carbapenem five patients had generalized seizures during concurrent valproate -b carbapenem treatment, including two with no prior history of seizures [408 ]. Meropenem is an enzyme inducer. Because of this pharmacokinetic interaction, concurrent use of these medications should be avoided. 

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