PHARMACOKINETICS OF ALPHA-METHYL-L-TRYPTOPHAN IN RHESUS-MONKEYS AND CALCULATION OF THE LUMPED CONSTANT FOR ESTIMATING THE RATE OF SEROTONINSYNTHESIS

We have determined several kinetic and pharmacokinetic parameters of L -tryptophan (Trp) and alpha-methyl-L-tryptophan (alpha MTrp) in the rh esus monkey from which the lumped constant for the alpha MTrp method o f estimating serotonin synthesis rates is calculated. alpha MTrp was i solated from DL-alpha MTrp using a chiral separation column with high performance liquid chromatography. alpha MTrp (50 mu g/kg) was adminis tered i.v. to four adult male rhesus monkeys and arterial blood sample s were collected for a 4-hr period. Plasma concentrations, as determin ed by high performance liquid chromatography with electrochemical dete ction, were best fitted by a tri-exponential equation. Plasma protein binding of Trp and alpha MTrp was determined by measuring concentratio ns in ultrafiltrates obtained at 30 degrees C. After a 2-hr adjusted r ate infusion of alpha MTrp designed to establish steady-state plasma c oncentrations, three adult male rhesus monkeys were killed by exsangui nation with perfused ice-cold saline. Brain/arterial plasma concentrat ion ratios of Trp and alpha MTrp and the Michaelis-Menten parameters f or tryptophan hydroxylase, EC 1.14.16.4, with Trp and alpha MTrp as in itiating substrates, were determined for seven brain regions. The lump ed constants determined for the different brain regions were not signi ficantly different from each other and indicate, that for modeling pur poses, the brain may be treated as a homogeneous area and the lumped c onstant given a single value, 0.18 +/- 0.05.