Pharmacokinetics of alpha-methyl-L-tryptophan in rhesus monkeys and calculation of the lumped constant for estimating the rate of serotonin synthesis

SE Shoaf and B Schmall

National Institute on Alcohol Abuse and Alcoholism, Laboratory of Clinical Studies, Bethesda, Maryland, USA.

We have determined several kinetic and pharmacokinetic parameters of L- tryptophan (Trp) and alpha-methyl-L-tryptophan (alphaMTrp) in the rhesus monkey from which the lumped constant for the alphaMTrp method of estimating serotonin synthesis rates is calculated. AlphaMTrp was isolated from DL-alphaMTrp using a chiral separation column with high performance liquid chromatography. AlphaMTrp (50 microgram/kg) was administered i.v. to four adult male rhesus monkeys and arterial blood samples were collected for a 4-hr period. Plasma concentrations, as determined by high performance liquid chromatography with electrochemical detection, were best fitted by a tri-exponential equation. Plasma protein binding of Trp and alphaMTrp was determined by measuring concentrations in ultrafiltrates obtained at 30 degrees C. After a 2-hr adjusted rate infusion of alphaMTrp designed to establish steady-state plasma concentrations, three adult male rhesus monkeys were killed by exsanguination with perfused ice-cold saline. Brain/arterial plasma concentration ratios of Trp and alphaMTrp and the Michaelis-Menten parameters for tryptophan hydroxylase, EC 1.14.16.4, with Trp and alphaMTrp as initiating substrates, were determined for seven brain regions. The lumped constants determined for the different brain regions were not significantly different from each other and indicate, that for modeling purposes, the brain may be treated as a homogeneous area and the lumped constant given a single value, 0.18 +/- 0.05.

Volume 277, Issue 1, pp. 219-224, 04/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics