The Effect of Fenfluramine on the Pulmonary Disposition of 5-Hydroxytryptamine in the Isolated Perfused Rat Lung: a Comparison with Chlorphentermine

Abstract

A possible mechanism for fenfluramine-induced pulmonary hypertension has been investigated. Fenfluramine, like chlorphentermine, may inhibit the pulmonary uptake and/or metabolism of 5-hydroxytryptamine (5-HT). This allows more 5-HT to remain in the pulmonary circulation, where it may exert a greater vasoconstrictor action resulting in pulmonary hypertension. Chlorphentermine has been shown to inhibit the uptake and metabolism of 5-HT. The effect of fenfluramine on the pulmonary disposition of [14C]5-HT has been investigated, in comparison with chlorphentermine, using a recirculating isolated perfused rat lung system. The pulmonary disposition of [14C]5-HT was assessed by measuring the change in [14C]5-HT concentration in the perfusion medium during the experiment and at the end, and the concentration in the lung at the end of the experiment. The concentration of 5-hydroxyindoleacetic acid, a metabolite of 5-HT, was measured in perfusate and lung samples. Mean pulmonary clearance of 5-HT for the control lung and lungs challenged with either fenfluramine (2.5 microM) or chlorphentermine (25 microM) was 4.514, 1.316 and 1.007 mL min(-1), respectively (n = 5). The concentration of 5-HT found in the lungs at the end of the experiment for the control and the lungs preloaded with fenfluramine or chlorphentermine was 695.05+/-9.69, 638.65+/-10.27 and 617.3+/-14.38 ng g(-1), respectively. Fenfluramine, like chlorphentermine, inhibited the pulmonary disposition of 5-HT resulting in an elevated perfusate level of 5-HT. This is a possible contributing mechanism for fenfluramine-induced pulmonary hypertension. The effect of fenfluramine was less pronounced than chlorphentermine.

Pharmacokinetics and Metabolism of Infused versus Inhaled Iloprost in Isolated Rabbit Lungs

“…Isolated lung models have repeatedly been employed for evaluating pharmacokinetic and pharmacodynamic parameters of agents of interest, mostly after admixture to the perfusion medium (Aislaitner et al, 1997;Valodia and Syce, 2000). In the current study, we focused on iloprost, a stable prostacyclin analog, and compared the inhalative to the intravascular route of administration.…”

Fenfluramine: A Review of Pharmacology, Clinical Efficacy, and Safety in Epilepsy

“…When FFA was used in high doses for obesity treatment, left-sided heart valves (mitral and aortic) were predominantly affected. This left-predominant valvulopathy may be due to FFA’s effect on the decreased pulmonary clearance of 5-HT, resulting in exposure to higher 5-HT levels on the left-sided valves [ 83 ]. 5-HT exposure may cause increased DNA synthesis and progression of cell cycles (activation of phospholipase C, protein kinase c, extracellular regulated kinase) in valve’s interstitial cells [ 81 , 84 ].…”