A pharmacodynamic model to investigate the structure-activity profile of a series of novel opioid analgesics.

A simple mathematical model of analgesia in the rat is developed and utilized to determine quantitative structure-activity relationships for a series of novel 4-anilidopiperidine opioids. The compounds tested (selected alkyl carboxyethyl esters attached at the one position of the piperidine ring) were designed for rapid inactivation by blood and tissue esterases. Model parameters included potency and rate constants for loss of pharmacodynamic effect by hydrolysis dependent and independent processes. A significant correlation is observed between duration of pharmacological effect in vivo and the rate constant for hydrolysis in human blood (r = 0.89). In vivo potency shows a moderate correlation with log P2 (r = -0.77). The validity of the model is shown by comparing model-based parameters which characterize potency and duration of effect in vivo with graphically derived parameters. Significant correlations are observed between model and graphically based estimates of potency (r = 0.75) and between model and graphically based estimates of duration of effect (r = 0.70). This model has potential application in studies of other classes of compounds in which hydrolytic cleavage limits duration of pharmacologic effect.

Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgetics.

In an effort to discover a potent ultrashort-acting mu opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent mu opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[(1-oxopropyl)phenylamino]-1-piperidinepropanoi c acid alkyl esters, were evaluated in vitro in the guinea pig ileum for mu opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent mu agonists in vitro, but depending upon the alkyl ester substitution the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The SAR with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.

Albuterol extended-release products: effect of food on the pharmacokinetics of single oral doses of Volmax and Proventil Repetabs in healthy male volunteers.

The absorption of albuterol from a single 4-mg oral dose of Volmax and Proventil Repetabs was investigated under both fasting and fed conditions in an open-label, randomized, four-period, crossover study in 24 healthy male volunteers. Blood was collected for determination of albuterol plasma concentrations by HPLC over 30 hours postdose. Twenty subjects were evaluable for data analysis. The mean Cmax for Volmax; administered after a meal was 19% lower than that of the drug administered in a fasting state (3.9 ng/mL vs. 4.8 ng/mL; P less than .01). An almost equivalent lowering of the mean Cmax (by 21%) was observed for Proventil Repetabs after administration with a meal versus fasting (4.2 ng/mL vs. 5.3 ng/mL; P less than .01). There were no significant differences between the two formulations in the degree of Cmax reduction due to the presence of food. The tmax occurred significantly later during the fed treatment for Volmax only (4.9 hours fasted vs. 6.4 hours fed; P less than .01). The lag time was significantly greater during the fed treatments for Volmax. No differences were observed in the area under the plasma concentration-time curve (AUC) for either formulation under fasting versus fed conditions, suggesting that the extent of absortion was not altered by food. Overall, food caused a more sustained release of albuterol from both Volmax and Proventil Repetabs.