Cenajek, D., Szczawińska, K., Chodera, A. and Nowakowska, E.: Development of tolerance to pethidine in rats, pretreated or not, with ß-naphtoflavone or SKF 525 A. Acta physiol, pol., 1988, 39 (4): 281-287. Tolerance to the analgesic effect of pethidine (PD) in rats, treated with a dose of 15 mg/kg of the compound twice daily at 12 h intervals for 1-3 weeks, was assessed using both, heat and current irritating stitnuli, (Tolerance could be detected earlier by the current irritating method, .than by the hot plate technique. Pretreatment with β -naphtoflavone did only slightly affect the development of tolerance to the antinofciceptive effect of (PD. In contrast after one week of treatment with SKF 525 А PD retained its1 analgesic effect. The prolonged pretreatment with SKF 525 A did not prevent the development of tolerance to the analgesic effect of PD.
Szczawińska, K., Cenajek-Musiał, D., Nowakowska, E. and Chodera, A.: Pharmacokinetic disposition of pethidine under tolerance. Acta physiol pol., 1989, 40 (4): 374-380. Under tolerance, evoked by multiple doses of pethidine (PD), the serum and brain tissue content of PD was related to diminished analgesic activity. Even though in tolerant rats no enhancement of PD biotransformation in the liver could be recognized (as followed by the measurement of hepatic esterase and N-demethylase activity), the amounts of both PD and nor-PD excreted in urine were increased under tolerance. The authors conclude that the faster disposition of PD may contribute to the development of tolerance.