Investigations into fed-state effects on phenytoin absorption and pharmacokinetics in dogs.

Abstract

Phenytoin is an antiepileptic agent for which co-administration with enteral nutrient supplements have resulted in variable drug plasma levels and inconsistent clinical response. Following oral dose, both variable absorption and clearance may contribute to drug plasma level deviations from the narrow therapeutic range. It was the goal of this thesis work to explore contributions to fasted versus fed-state phenytoin plasma levels in dogs. The dog represents a good animal model for this investigation since its GI physiology is similar to human while a high-capacity canine phenytoin elimination pathway provides drug plasma level sensitivity to variable absorption. Preliminary studies were performed comparing drug plasma levels following oral phenytoin administered with equal volumes of water, glucose and an enteral nutrient solution. Drug plasma levels were lower in the fasted state than with glucose and highest with enteral nutrient administered at a similar caloric density. Higher plasma levels correlated with longer gastric emptying times as measured by radiotelemetry. However, bypassing the stomach by drug/nutrient duodenal co-administration produced drug plasma levels in the same treatment order suggesting other fed-state contributions. Oral administration of phenytoin in conjunction with duodenal infusion of isocaloric treatments of glucose, casein hydrolysate, or sodium oleate versus saline control resulted in significantly higher drug levels only with sodium oleate. Ileal fluid volume measurement showed substantial GI secretions and IV administration of a CCK antagonist in a single study blocked the oleate effect on drug plasma levels. Intravenous phenytoin in the fed-state yielded no changes in phenytoin elimination half life or area under the plasma level versus time curve. However, both glucose and oleate fed states perturbed steady-state phenytoin plasma levels from IV drug infusion while casein hydrolysate had no effect. An increase in the extent of drug dissolution as a function of fed-state increases in gastric emptying time provide a partial explanation for fed-state effects on this poorly soluble drug. Additional fed-state effects on dissolution rate were investigated in vitro. Rotating paddle and basket studies showed variable surface area could contribute to variable dissolution rates. Rotating disc experiments showed that fed-state bile salt concentrations and lipid emulsion increased phenytoin dissolution flux by increasing drug solubility.