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Toxicokinetic comparison of a CCK‐B/gastrin receptor antagonist given orally and intravenously
Author(s) -
Dethloff Lloyd A.,
Hinton Joanna P.
Publication year - 1997
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199704)40:4<292::aid-ddr2>3.0.co;2-e
Subject(s) - cmax , toxicokinetics , gastrin , medicine , pharmacokinetics , chemistry , antagonist , endocrinology , pharmacology , receptor , secretion
CI‐988 is a dipeptoid CCK‐B/gastrin receptor ligand with potential clinical indications in anxiety and panic disorder. The toxicity and toxicokinetics of CI‐988 given orally (PO) or intravenously (IV) were evaluated to delineate the relationship between administered dose, plasma CI‐988 concentrations, and target organ changes in order to establish appropriate safety margins for human clinical studies. CI‐988 was given to monkeys PO at doses of 5, 25, and 75 mg/kg/day or IV at doses of 0.2, 2, and 5 mg/kg/day for up to 4 weeks. When given PO, CI‐988 caused dose‐related, mild to moderate gastric gland degeneration at 25 and 75 mg/kg. There were no adverse effects at 5 mg/kg. Associated with these doses were mean (± standard deviation) maximum plasma concentrations (Cmax) of 5.6 ± 4.9, 12.9 ± 6.2, and 10.4 ± 5.1 ng/mL and areas under the plasma concentration vs. time curve (AUC) of 24.1 ± 14.2, 63.8 ± 27.1 and 100 ± 43 nghmL –1 , respectively. Given IV, CI‐988 had no effect on the gastric mucosa despite achieving plasma concentrations as high as 239 ± 116, 2,250 ± 1,230, and 5,490 ± 1,890 ng/mL approximately 5 min postdose at 0.2, 2, and 5 mg/kg, respectively. The AUCs associated with IV CI‐988 at 5 mg/kg were at least 10‐fold greater than those associated with PO doses shown to induce gastric lesions. These data indicate that plasma CI‐988 concentrations are not predictive for, or directly associated with, gastric gland degeneration and suggest that these mucosal changes may be related to local, rather than systemic, exposure to CI‐988. Accordingly, safety margins for CI‐988 appear to be more appropriately based upon administered dose than upon plasma concentrations. Drug Dev. Res. 40:292–298, 1997. © 1997 Wiley‐Liss, Inc.