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Quantification of imipenem's primary metabolite in plasma by postcolumn chemical rearrangement and UV detection
D G Musson1, R Hajdu, W F Bayne
1Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
Abstract:
Imipenem (thienamycin formamidine) is an antibiotic active against a broad spectrum of bacteria. Its primary metabolite arises from cleavage of the lactam ring. The metabolite can be formed in-vitro by acid-catalyzed or enzymatic hydrolysis. In animals and man, this metabolite can be generated systemically as well as in the kidneys following the excretion of imipenem into the urine. In man, this dehydropeptidase-catalyzed renal metabolism is minimized by the coadministration of cilastatin, a competitive inhibitor. A specific HPLC assay has been developed to evaluate the disposition of this metabolite in humans having normal or end-stage renal function. The assay employs ion-pair, reversed-phase chromatography, and post-column acid treatment of the analyte for ultraviolet detection.
Insights
Imipenem antibiotic metabolism creates a primary metabolite cleared by kidneys. Coadministration with cilastatin minimizes this renal metabolism in humans, as evaluated by a novel HPLC assay.
Area of Science:
- Pharmacology
- Drug Metabolism
- Analytical Chemistry
Background:
- Imipenem is a broad-spectrum antibiotic.
- Its primary metabolite results from lactam ring cleavage, occurring via acid or enzymatic hydrolysis.
- This metabolite is generated systemically and renally, especially after imipenem excretion into urine.
Purpose of the Study:
- To develop and validate a specific High-Performance Liquid Chromatography (HPLC) assay.
- To evaluate the disposition of the imipenem metabolite in humans with normal and end-stage renal function.
Main Methods:
- Development of a specific HPLC assay.
- Utilizing ion-pair, reversed-phase chromatography.
- Employing post-column acid treatment for ultraviolet detection.
Main Results:
- A specific HPLC assay was successfully developed.
- The assay allows for the evaluation of imipenem metabolite disposition.
- Renal metabolism of imipenem is minimized by coadministration with cilastatin.
Conclusions:
- The developed HPLC assay is suitable for assessing imipenem metabolite pharmacokinetics.
- Coadministration with cilastatin effectively reduces renal imipenem metabolism in humans.
- Understanding imipenem metabolite disposition is crucial for patients with varying renal function.