title: Metabolism by N-acetyltransferase 1 in vitro and in healthy volunteers: a prototype for targeted inhibition.
abstract: 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 microM. 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 microM. 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.
authors.affiliation: Division of Clinical Pharmacology and Medical Toxicology, Building 53, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
authors.forename: Louis R
authors.initials: LR
authors.lastname: Cantilena
authors.forename: Aspandiar G
authors.initials: AG
authors.lastname: Katki
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Klecker
authors.forename: Jerry M
authors.initials: JM
authors.lastname: Collins
mesh_terms: D000328:Adult; D010131:Aminosalicylic Acid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D001191:Arylamine N-Acetyltransferase / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D046508:Culture Techniques / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems / Q000379:methods* / Q000639:trends*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D013420:Sulfamethoxazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D007527:Isoenzymes; C021281:N(1)-acetylsulfamethoxazole; D010131:Aminosalicylic Acid; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; D013420:Sulfamethoxazole