Propoxyphene and norpropoxyphene kinetics after single and repeated doses of propoxyphene.

Plasma concentrations of propoxyphene (P) and its pharmacologically active metabolite norpropoxyphene (NP) were determined in normal subjects after single 130-mg oral doses and during and after 13 consecutive oral doses of 130 mg P, and in former heroin addicts who were maintained on 900 to 1200 mg of P per day. The data were analyzed using a first-pass elimination pharmacokinetic model. Both P and NP cumulated during repeated dosing to levels 5 to 7 times those after the first dose. In contrast, "maintenance" patients exhibited steady-state trough plasma NP cumulation that exceeded that of P by a factor of 13. Several changes in P and NP kinetics occurred during repeated dosing with P to the normal subjects: P clearance decreased from 994 to 508 ml/min, NP clearance decreased from 454 to 2210 ml/min, P half-life (t 1/2) increased from 3.3 to 11.8 hr, NP t 1/2 increased from 6.1 to 39.2 hr, and area under the concentration time curves for P and NP were doubled. These changes in kinetics during repeated dosing resulted in more extensive cumulation of P and NP than would be predicted from the single-dose kinetic profile. Changes in the extent of first-pass elimination of P result in variability in plasma P and NP that may contribute to P-induced toxicity.