Influence of clofibrate on serum triptophan in man

Abstract

Summary. The effect of clofibrate on free and bound tryptophan levels was tested in 8 volunteers, 5 of whom were hospitalised. Comparing the effects of the drug, administered for 5 days, with those of a placebo, given for 5 further days, after an interval of 2 days, it was observed that clofibrate lowered total plasma tryptophan by 50--70~o in all subjects. The decrease is in the bound fraction and probably reflects a displacement due to the high protein binding affinity of the drug. At the same time plasma free tryptophan values increase significantly.These data confirm our previous observations in the rat, demonstrating a decrease of bound plasma tryptophan and an increase of brain tryptophan and 5-HIAA levels, and supporting the hypothesis that clofibrate increased the availability of tryptophan to brain tryptophan hydroxylase, thus stimulating serotonin synthesis.Key words: Clofibrate --Free and bound plasma tryptophan --Serotonin synthesis.Clofibrate (p-chlorophenoxyisobutyrate) (CPIB) is a commonly used drug for the management of hyperlipoproteinemias [2,15]. It is highly bound to plasma proteins and has a relatively long half-life, i.e. 10--14 hrs, in man [22]. It displaces oral anticoagulants from albumin binding sites [18]. It was our purpose to determine the drug's ability to displace tryptophan from its plasma binding sites, thus increasing the availability of free tryptophan. Tryptophan is, in fact, the only circulating amino acid highly bound to serum proteins [13]; the tryptophan pool in brain is controlled by the free fraction of serum tryptophan [11]. Moreover, there is ample evidence that the rate of synthesis of 5-hydroxytryptamine (5-HT) in brain is regulated principally by brain tryptophan, since the availability of this amino acid in the nervous tissues is considerably below the Km of the first enzyme in 5-tIT biosynthesis, tryptophan hydroxylase [8]. Treatments which cause increased synthesis of brain 5-HT all lead to significant increases in the concentration of brain tryptophan [20].