¹McNeil Consumer & Specialty Pharmaceuticals, University of Washington, Fort Washington, PA, USA

Abstract

We assessed the pharmacokinetics (PK) and metabolism of 1, 1.5, and 2 g APAP dosed every 6 h for 3 days (4, 6, and 8 g/d) using a double-blinded, placebo-controlled, 3-regimen study design. Subjects were divided into 2 groups that received: (I) placebo (n=6) or APAP (n=12) at 4 then 6 g/d; (II) placebo (n=6) or APAP (n=12) at 4 then 8 g/d. Safety and hepatic function were monitored daily. Blood samples were collected after the first and last dose of each dosing regimen, and urine was collected for 24 hours on Day 3 of dosing. PK results showed that APAP plasma concentrations did not accumulate with repeat doses, and that steady-state concentrations were linearly related to dose. Plasma metabolite data showed an unexpected increase in production of the major metabolite APAP-glucuronide and a decrease of APAP-sulfate between the first and last doses for 4, 6, and 8 g/d. The urine metabolite pattern changed with dose level: a higher amount (67%) of APAP-glucuronide was produced at 8 g/d compared with 59% and 61% for 4 and 6 g/d, and a lower amount (11%) of APAP-sulfate was produced at 8 g/d compared with 19% and 14% for 4 and 6 g/d. The findings are consistent with enzyme induction of glucuronidation and saturation of the sulfate pathway. Patterns of the other metabolites (thiols and catechol) did not differ substantially with dose. All doses were well tolerated and all hepatic aminotransaminase values stayed within normal limits.