BUCCAL ABSORPTION OF FENTANYL IS PH-DEPENDENT IN DOGS

Analgesia and sedation have been achieved noninvasively by fentanyl ad ministration through the oral and nasal mucosa. In theory, the transmu cosal bioavailability and absorption of fentanyl could be improved by converting more fentanyl to the unionized form by adjusting the surrou nding pH. The authors tested this hypothesis in dogs. Methods: Under g eneral anesthesia, each of six mongrel dogs was given fentanyl on repe ated occasions, first intravenously (once), then by application to the buccal mucosa (six times). Buccal fentanyl administration was accompl ished by placement of a pH-buffered solution of fentanyl into a specia lly constructed cell, which was clamped to the dog's buccal mucosa for 60 min. Fentanyl solutions with pHs of 6.6, 7.2, and 7.7 were studied to span a tenfold difference in the unionized fraction of fentanyl. F emoral arterial blood samples were sampled frequently and analyzed for fentanyl using a radioimmunoassay. Peak plasma concentration and the time of its occurrence for each buccal study were noted from the plasm a concentration verses time profile. Terminal elimination half-life, b ioavailability, and permeability coefficients were calculated using st andard pharmacokinetic techniques. Results: The variables peak plasma concentration, bioavailability, and permeability coefficient increased three- to fivefold as the pH of the fentanyl buccal solution increase d and more fentanyl molecules became unionized. There was no differenc e in terminal elimination half-life after intravenous fentanyl (244 +/ - 68 min) or buccal fentanyl administration (pH 7.7, 205 +/- 89 min; p H 7.2, 205 +/- 65 min; pH 6.6, 196 +/- 48 min). In all buccal studies regardless of pH, time to peak plasma concentration occurred within 10 min of removal of the fentanyl solutions from the buccal mucosa. Conc lusions: The buccal absorption, bioavailability, and permeability of f entanyl are markedly increased as the pH of the fentanyl solution beco mes more basic. Most likely, this is because of an increase in the fra ction of unionized fentanyl.