Propoxyphene and norpropoxyphene kinetics after single and repeated doses of propoxyphene

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Abstract
[P (dextropropoxyphene) is a widely prescribed oral analgesic. Because the drug has been associated with poisonings and deaths, concern has been expressed over its safeness.] Plasma concentrations of 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 900-1200 mg P/day. The data were analyzed using a 1st-pass elimination pharmacokinetic model. Both P and NP cumulated during repeated dosing to levels 5-7 times those after the 1st dose. 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 210 ml/min, P half-life (t1/2) increased from 3.3 to 11.8 h, NP t1/2 increased from 6.1 to 39.2 h, and area under the concentration time curves from P and NP were doubled. These changes in kinetics during repeated dosing apparently resulted in more extensive cumulation of P and NP than would be predicted from the single-dose kinetic profile. Changes in the extent of 1st-pass elimination of P apparently resulted in variability in plasma P and NP that may contribute to P-induced toxicity.