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Metabolism by N-Acetyltransferase 1 In Vitro and in Healthy Volunteers: A Prototype for Targeted Inhibition

From the Division of Clinical Pharmacology and Medical Toxicology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, and the Laboratory of Clinical Pharmacology, Food and Drug Administration, Rockville, Maryland.

Inhibition of drug metabolism is generally avoided but can be useful in limited circumstances, such as reducing the formation of toxic metabolites. Acetylation is a major pathway for drug elimination that can also convert substrates into toxic species, including carcinogens. Sulfamethoxazole, a widely used antibiotic, is metabolized via arylamine N-acetyltransferase 1. p-Aminosalicylate, used for antitubercular treatment, is also metabolized by N-acetyltransferase 1 and could potentially inhibit sulfamethoxazole metabolism. Human hepatocytes from 4 donors were incubated in vitro with sulfamethoxazole and paminosalicylate at clinically achievable concentrations. p-Aminosalicylate competitively reduced the acetylation of sulfamethoxazole in vitro by 61% to 83% at 200 µM. Four healthy volunteers were studied following doses of 500 mg sulfamethoxazole either alone or during administration of paminosalicylate (4 g ter in die). Plasma concentrations of paminosalicylate exceeded 100 µM. With each subject as his or her own control, p-aminosalicylate reduced by 5-fold the ratio of plasma concentrations of acetylsulfamethoxazole relative to parent drug (P < .001). Metabolic drug-drug interaction studies in vitro successfully predicted inhibition of acetylation via N-acetyltransferase 1 in vivo. Although no specific toxic species was investigated in this work, the potential was demonstrated for improving the therapeutic index of drugs that have toxic metabolites.

Key Words: NAT1 • p-aminosalicylate • drug metabolism • drug interactions • sulfamethoxazole

Address for reprints: Louis R. Cantilena, Jr, MD, PhD, Division of Clinical Pharmacology and Medical Toxicology, Building 53, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814.

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