Eur J Clin Pharmacol (1985)29:79-84 European Journal of Clinical Pharmacology © Springer-Verlag 1985 Dextropropoxyphene Kinetics After Single and Repeated Oral Doses in Man K. Brosen 1, L. F. Gram 1, J. Schou:, N. E. Larsen 3, and P. Thayssen 4 1Departmentof Clinical Pharmacology, Odense University, 2Instituteof Pharmacology, Universityof Copenhagen, 3Clinical Pharmacological Laboratory,Departmentof ClinicalChemistry,Glostrup Hospital, and 4Departmentof Internal MedicineB, Odense UniversityHospital, Odense Denmark Summary. The kinetics of dextropropoxyphene (DP) and its main metabolite norpropoxyphene (NP) were studied in 6 healthy male subjects after a single oral dose of 195 mg DP HC1, and during and after 12 dai- ly single oral doses of 195 mg DP HC1. The kinetics varied up to five-fold between individuals after the single dose, the apparent mean elimination half-life (t~) was 16 h for DP and 29 h for NR The mean ap- parent overall plasma clearance (CL) for DP was 2.61/min. There was no systematic difference in DP clearance between the single and multiple doses, but the accuracy of individual predictions from single to multiple doses was poor, probably because of impre- cise determinations of the AUC and t~ in the single dose experiments. The individual correlation be- tween single and multiple dose kinetics was good for NP, although the predicted plasma levels during steady state were significantly higher than the ob- served levels (mean AUCss/AUCsd: 0.81). There was no sign of saturation kinetics on repeated adminis- tration. In fact, autoinduction, resulting in signifi- cantly lower plasma concentrations after treatment for 1 week was found for NP and was indicated for DE On discontinuing DP after 12 days of treatment, the apparent mean tl/2 of DP was 23 h and of NP 25 h. Key words, dextropropoxyphene, norpropoxyphene; pharmacokinetics, single dose, multiple dose, predic- tion, saturation, auto-induction Gram et al. 1979 and 1980; Inturrisi et al. 1982). After oral administration DP is subject to extensive "first- pass" metabolism in the liver (Wolen et al. 1971b; Perrier and Gibaldi 1972; Gram et al. 1979) and very little is excreted unchanged (McMahon et al. 1971 and 1973). Eight metabolites have been identified in human urine (McMahon et al. 1974), of which the most important is norpropoxyphene NP (McMahon et al. 1971 and 1974). The elimination tl/2both of DP and NP is much longer than was initially claimed. It is of the order of 12-15 h for DP and 25-40h for NP (Wolen et al. 1975; Schou et al. 1978; Gram et al. 1979). Slow dis- tribution into a deep peripheral compartment may explain some of the discrepancies (Gram et al. 1984). Daily intake would be expected to result in accumu- lation both of DP and especially NR Animal studies have shown that CNS toxicity af- ter overdosage of DP is attributable to the parent drug, while both DP and NP contribute to cardiotox- icity (Nickander et al. 1977; Lund-Jacobsen 1977; Holland 1978; Steinburg 1978). In view of the seri- ous and often unpredictable toxicity in humans (Finkle et al. 1976), the present study was undertaken in order to examine the pharmacokinetics of DP and NP after single and repeated oral doses. A further aim of the study was to find out if single dose pharmacokinetics could be used to predict the steady state plasma levels of DP and NP after multi- ple doses. The metabolism and pharmacokinetics of the oral analgetic drug, dextropropoxyphene (DP), have been extensively studied (Wolen et al. 1971 a and b; McMahon et al. 1971; Wagner et al. 1972a and b; Verebely et al. 1974; Wolen et al. 1975; Schou 1978; Subjects and Methods After receiving verbal and written information, 6 male students, aged 20-28 years, consented to parti- cipate as paid volunteers. Prior to the study each sub- ject was shown to be healthy by clinical examination