Calcitonin gene-related peptide and somatostatin releases correlated with the area under the lafutidine concentration-time curve in human plasma.
OBJECTIVE
To examine the effects of the histamine H(2)-receptor antagonist, lafutidine, at clinical dosage (10 mg tablet after a standardized meal) on plasma levels of the gastrointestinal peptides, calcitonin gene-related peptide (CGRP), somatostatin and gastrin.


METHODS
Six healthy male volunteers ate a standardized meal, and received either lafutidine orally at a dose of 10 mg or water only (control). Blood samples were taken before and up to 4 h after the drug administration. Plasma lafutidine concentrations were determined by high pressure liquid chromatography. Pharmacokinetic analysis of lafutidine was performed using one-compartmental model. The levels of immunoreactive substances of plasma CGRP, somatostatin and gastrin were measured by enzyme immunoassay, and the amount of peptide release was calculated by the trapezoidal method. Lafutidine significantly increased plasma CGRP levels at 1, 1.5, 2.5 and 4 h and the total amount of CGRP release (192 +/- 14.0 pg.h/mL) compared with the control group (128 +/- 21.5 pg.h/mL).


RESULTS
Lafutidine significantly increased the plasma somatostatin levels at 1 and 1.5 h, and the total amount of somatostatin released (107 +/- 18.2 pg.h/mL) compared with the control (78.4 +/- 7.70 pg.h/mL). The area under the drug concentration-time curve (AUC) from 0 to 4 h after administration correlated well with the Delta-CGRP and Delta-somatostatin release but not with total amount of gastrin released. However, plasma gastrin levels were significantly elevated at 1.5 h after drug administration.


CONCLUSIONS
Lafutidine at clinical dosage increases plasma CGRP and the somatostatin. The amounts released correlated with the AUC of lafutidine in humans. These results suggest that the increased release of CGRP and somatostatin may contribute to its gastroprotective and anti-acid secretory effect.
Ikawa
K
K
Department of Clinical Pharmacotherapy, Hiroshima University, Hiroshima, Japan. ikawak@hiroshima-u.ac.jp
Shimatani
T
T
Azuma
Y
Y
Inoue
M
M
Morikawa
N
N
D000081:Acetamides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D015740:Calcitonin Gene-Related Peptide / Q000097:blood*; D005753:Gastric Mucosa / Q000378:metabolism; D005755:Gastrins / Q000097:blood*; D006207:Half-Life; D006635:Histamine H2 Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D013004:Somatostatin / Q000097:blood*; D013270:Stomach / Q000187:drug effects
D000081:Acetamides; D005755:Gastrins; D006635:Histamine H2 Antagonists; D010880:Piperidines; D011725:Pyridines; C076948:lafutidine; D013004:Somatostatin; D015740:Calcitonin Gene-Related Peptide