Kinetics and dynamics of the peripheral neurokinin-1 receptor antagonist SLV317 in healthy individuals.
OBJECTIVE
To investigate the pharmacokinetics and the pharmacodynamic effects in dorsal hand veins of the neurokinin-1 receptor antagonist SLV317.


METHODS
In a randomized, double-blind, placebo-controlled cross-over study 19 healthy men received a single oral dose of SLV317 or placebo. Blood samples were collected for analysis of SLV317 plasma concentrations and the inhibition of the venodilator response to substance P was evaluated using the hand vein compliance method.


RESULTS
Administration of 250 mg SLV317 as an oral solution was well tolerated and resulted in mean peak plasma concentrations (+/- SEM) of 77 +/- 9 ng ml(-1) within 47 +/- 3 min; the mean half-life was 9.9 +/- 1.6 h. In hand veins preconstricted with phenylephrine, local infusion of substance P resulted in a mean venodilation of 56 +/- 8% and 49 +/- 6% (P = 0.91) before administration of SLV317 or placebo, respectively. SLV317 caused a substantial inhibition of substance P-induced venodilation, whereas placebo had no effect (P < 0.001). The maximum antagonizing effect of SLV317 averaged 95 +/- 8% and was observed after 1.47 +/- 00.24 h. Correspondingly, the mean area under the effect curve after administration of SLV317 [278 +/- 67% h(-1); 95% confidence interval (CI) 198, 358] was significantly higher compared with placebo (49 +/- 12% h(-1); 95% CI -24, 122; P < 0.001).


CONCLUSIONS
This study demonstrates that the neurokinin-1 receptor antagonist SLV317 is an orally active and highly effective antagonist of substance P-induced effects in humans.
Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, Medical Faculty, University of Heidelberg, Germany.
Christiane
C
Hesse
Steffen P
SP
Luntz
Heike
H
Siedler
Kristina
K
Unnebrink
Gerd
G
Mikus
Marianne
M
de Bruijn
Edu
E
Zondag
Michiel
M
de Vries
Monika
M
Seibert-Grafe
Walter E
WE
Haefeli
D000284:Administration, Oral; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006225:Hand / Q000098:blood supply; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D013373:Substance P / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D014680:Veins
D007211:Indoles; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines; C513054:SLV317; D014665:Vasodilator Agents; D013373:Substance P