Pharmacology of rising oral doses of 5-hydroxytryptophan with carbidopa.
5-hydroxytryptophan (5-HTP) is a direct 5-hydroxytryptamine (5-HT) precursor used to assess central serotonergic function. Its use has been limited by a narrow window between neuroendocrine changes and side effects, and variable kinetics related to inconsistent administration modes. By combining 5-HTP with carbidopa (CBD), increased bioavailability for brain penetration and decreased peripheral side effects would be expected, due to reduced peripheral decarboxylation of 5-HTP to 5-HT. A double-blind, placebo-controlled, single rising dose, four-way crossover trial with placebo randomisation was performed in 15 healthy male volunteers to investigate the neuroendocrine dose-response relationship at various 5-HTP levels; the tolerability and subjective effects of oral 5-HTP at 100, 200 and 300 mg combined with CBD and the pharmacokinetic properties of the 5-HTP/CBD-challenge. Dose-dependent increases in average cortisol concentrations were observed. Mean response (area-under-the-curve) over the first 4 hours (SD): 172.0 nmol/L (22.3) for placebo, 258.3 nmol/L (72.6) for 100 mg, 328.47 nmol/L (84.6) for 200 mg and 387.3 nmol/L (82.4) for 300 mg 5-HTP. Similar dose-dependent increases for prolactin were seen while adreno-corticotrophic hormone response was more variable. 5-HTP kinetics were adequately described using a one-compartment model with first-order absorption and a lag time (mean oral clearance 28 L/h interindividual coefficient of variation 31%). Nausea and vomiting occurred dose-dependently as most frequent side effects, resulting in dose-related dropout of 6.6% at 100 mg and 45.5% at 300 mg 5-HTP. Orally administered 5-HTP combined with CBD is an effective serotonergic challenge test, exhibiting dose-related plasma concentrations and neuroendocrine responsiveness. Frequent occurrence of nausea and vomiting limits the applicability of this challenge at 5-HTP doses above 100 mg.
Smarius
L J C A
LJ
Centre for Human Drug Research and Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands.
Jacobs
G E
GE
Hoeberechts-Lefrandt
D H M
DH
de Kam
M L
ML
van der Post
J P
JP
de Rijk
R
R
van Pelt
J
J
Schoemaker
R C
RC
Zitman
F G
FG
van Gerven
J M A
JM
Gijsman
H J
HJ
D006916:5-Hydroxytryptophan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000284:Administration, Oral; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000339:Affect / Q000187:drug effects; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002230:Carbidopa / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D009325:Nausea / Q000139:chemically induced; D010352:Patient Dropouts / Q000706:statistics & numerical data; D011388:Prolactin / Q000097:blood; D014839:Vomiting / Q000139:chemically induced; D055815:Young Adult
D018687:Antidepressive Agents, Second-Generation; D004791:Enzyme Inhibitors; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D006916:5-Hydroxytryptophan; D002230:Carbidopa; D006854:Hydrocortisone