Effect of Meals on the Kinetics of Etretinate

Abstract

Eight healthy men received 100 mg oral doses of etretinate separated by two-week washout periods in an open, randomized, crossover study. Etretinate was administered during a complete fast, with a standard high fat breakfast, a standard high carbohydrate breakfast, and 16 ounces of whole milk. Plasma samples were obtained at specific times over a 48-hour period. Plasma concentrations of etretinate as well as two of its major metabolites were determined by a specific, reverse-phase, high-performance liquid chromatography method. Plasma concentrations of etretinate were greater when administered with a high fat meal and whole milk compared to ingestion with a high carbohydrate meal or during a complete fast. In contrast, there was no increase in the plasma concentrations of the active metabolites following any of the meals. These data indicate that chronic dosing of etretinate with milk or a high fat meal compared with fasting conditions will result in higher concentrations of etretinate, which may ultimately lead to higher metabolite concentrations.

Overview of Recent Clinical Pharmacokinetic Studies with Acitretin (Ro 10-1670, Etretin)

“…it can be clearly seen that acitretin was also absorbed more consistently with food and therefore patients are recom mended to take acitretin with the main meal of the day. The increased bioavailability of acitretin in the presence of food is comparable to that observed for etretinate [8] and is most probably due to facilitated absorption of the highly lipophilic unchanged drug.…”

“…However, the extent of obesity was not evaluated in this study and a possible relationship between plasma concen trations and obesity, as observed in the rat [15], remains to be elucidated in man. There was also no significant influence of gender on plasma concentrations of acitretin during treatment with acitretin : average C mj"ss in male pa tients was similar to that in females (study 8).…”

Effect of Dietary Fat Content on Oral Bioavailability of Menatetrenone in Humans

“…Since no volunteers complained of steatorrhea after any meal, this phenomenon would not be due to lipid malabsorption. An excessively fatty meal may prolong the emptying time of the stomach, resulting in the lower first peak of absorption after meal D than after meal C. In fact, many volunteers complained of prolonged abdominal fullness especially after meal D. Interestingly, an increase in the fat content of a meal from 16 g to 111 g was reported not to enhance retinoid absorption any further, 11 suggesting also the presence of the optimum fat content for enteric bioavailability of retinoid.…”

Physicochemical and Physiological Mechanisms for the Effects of Food on Drug Absorption: The Role of Lipids and pH

“…146 The oral bioavailability of etretinate increased 3-5-fold when administered with a high fat meal or milk compared with fasted administration. 146,147 The amount of metabolite formed (defined by the area under the metabolite plasma concentration-time curve) was unchanged after administration of parent compound in either the fed or fasted state, indicating that coadministration of etretinate with food significantly increased the amount of parent drug absorbed, but appeared to reduce the extent of metabolism. Due to the structural similarity with Vitamin A, it was speculated that solubilization of etretinate in the postprandial intestinal environment may have facilitated both portal blood absorption and lymphatic transport.…”