Premium
Metabolism by N‐Acetyltransferase 1 In Vitro and in Healthy Volunteers: A Prototype for Targeted Inhibition
Author(s) -
Cantilena Louis R.,
Katki Aspandiar G.,
Klecker Raymond W.,
Collins Jerry M.
Publication year - 2004
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270004270224
Subject(s) - chemistry , acetylation , in vitro , sulfamethoxazole , in vivo , pharmacology , drug , metabolism , acetyltransferase , drug metabolism , antibiotics , biochemistry , biology , microbiology and biotechnology , gene
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 p‐aminosalicylate 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 p‐aminosalicylate (4 g ter in die). Plasma concentrations of p‐aminosalicylate 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.