Pharmacologic Actions

The action of dexfenfluramine hydrochloride in treating obesity is primarily via decreased caloric intake associated with increased serotonin levels in brain synapses. Dexfenfluramine hydrochloride is a serotonin reuptake inhibitor and releasing agent. In vitro studies have confirmed the dual serotoninergic mechanism of action of dexfenfluramine by demonstrating that the drug inhibits serotonin reuptake by axon terminals and causes the release of serotonin from synaptosomes. In animals, the reduced caloric intake and the loss in body weight elicited by dexfenfluramine is associated with release of serotonin from presynaptic axon terminals in the brain, inhibition of neuronal serotonin reuptake, and therefore, an increase of serotonin receptor activation. This results in an enhancement of serotoninergic transmission in the centers of feeding behavior, located in the ventro-medial nucleus of the hypothalamus. In rats, enhanced serotoninergic transmission induced by dexfenfluramine selectively suppressed appetite for carbohydrates which resulted in reduction of food consumption when the dietary carbohydrate to protein ratio was high. Unlike amphetamines and other serotonin-active agonists and antagonists, dexfenfluramine neither enhances nor suppresses dopamine-mediated neurotransmission.

In clinical trials, dexfenfluramine treatment in conjunction with a reduced-calorie diet is associated with a reduction in appetite and may slow gastric emptying. These and other actions may contribute to the reduction in caloric consumption associated with dexfenfluramine. In one clinical trial, dexfenfluramine was shown to preferentially decrease carbohydrate consumption at meals and to manage carbohydrate craving between meals by decreasing the consumption of snack foods with a high carbohydrate content in patients who frequently snack on such foods.

Pharmacokinetics and Metabolism

Systemic Bioavailability: Dexfenfluramine is completely absorbed after oral dosing, with a systemic bioavailability of about 68% because of first pass metabolism by the liver. In studies in which patients received a single 30-mg oral dose of dexfenfluramine, mean peak plasma concentrations of dexfenfluramine ranged between 11 and 41 ng/mL in individual patients after 1.5 to 8.0 hours. The average terminal elimination half-life of plasma dexfenfluramine ranged from 17 to 20 hours, and the average total body clearance of dexfenfluramine was 691.9 mL/min. In man, following doses of 15 mg dexfenfluramine twice a day for 15 days, mean maximal plasma dexfenfluramine concentrations ranging from 15 to 92 ng/mL were observed, and steady-state plasma levels were achieved 8 days after the initial dose. The average steady-state plasma concentrations were somewhat lower than predicted by single-dose pharmacokinetics and the average time to steady-state was longer than the predicted 4 to 5 days. The major active metabolite, d-norfenfluramine, accumulated to maximal plasma concentrations of about 26 ng/mL, with steady-state plasma levels occurring at about 9 days. The d-norfenfluramine plasma half-life is estimated to be 32 hours. After reaching steady-state levels, there was no evidence of increasing concentrations of dexfenfluramine or d-norfenfluramine in plasma during 12 months of dosing. Following administration of single 30-mg, 40-mg, and 60-mg doses of dexfenfluramine to healthy volunteers, dexfenfluramine C_max values of 25 ng/mL, 33 ng/mL, and 51 ng/mL and area-under-the-curve_0-t values of 144 ng·hr/mL, 191 ng·hr/mL, and 275 ng·hr/mL, respectively, were found. In a dose response study of dexfenfluramine involving obese patients treated for 12 weeks, dexfenfluramine C_min values of 24 ng/mL at a dose of 15 mg twice daily and 58 ng/mL at a dose of 30 mg twice daily were observed. These data suggest that plasma concentrations of dexfenfluramine increase in proportion to the administered dose.

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