Development of HPLC plasma assays for CAM 4515 and CAM 4750, two new nonpeptide tachykinin antagonists, and application to bioavailability studies.
CAM 4515 and CAM 4750 are new nonpeptide tachykinin NK1 receptor antagonists with different lipophilicities. Two separate, simple, and sensitive HPLC methods for the quantitation of these two compounds in plasma and the evaluation of their oral bioavailability in rats were developed and validated. Extraction of CAM 4515 from plasma involved protein precipitation with acetonitrile, while that for CAM 4750 involved a one-step liquid-liquid extraction with methylene chloride. The analytes in extracts were chromatographed on a C18 column using two different separation buffers, 47% 0.02 M sodium citrate (pH 3.5)-53% acetonitrile for CAM 4515 and 59% 0.02 M potassium phosphate dibasic (pH 7.0)-41% acetonitrile for CAM 4750, and both compounds were detected by fluorescence (excitation 278 nm; emission 342 nm). Stability profiles of both drugs at -20 degrees C or room temperature in plasma and in reconstituted buffers were good. The limit of quantitation for both drugs was 5 ng ml-1 with good linearity from 5 to 1000 ng ml-1 using 100-200 microliters of plasma. Excellent precision (relative standard deviation < 8.3%) and accuracy (relative error +/- 9.2%) were observed for both CAM 4515 and CAM 4750. Oral bioavailability studies were conducted for each compound in rats receiving a p.o. dose of 20 mg kg-1 and an i.v. dose of 5 mg kg-1. The absolute oral bioavailability of CAM 4750 (80%) was estimated to be 40-fold greater than that of CAM 4515 (2%). The experimental results suggest that incorporation of a pyridine group into the structural backbone may greatly improve bioavailability.
Van Noord
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Department of Pharmacokinetics and Drug Metabolism, Parke-Davis Pharmaceutical Research, Ann Arbor, MI 48105, USA.
Wright
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DS
Kuo
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BS
D000284:Administration, Oral; D000818:Animals; D001572:Benzofurans / Q000097:blood* / Q000493:pharmacokinetics*; D001682:Biological Availability; D002219:Carbamates / Q000097:blood* / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004355:Drug Stability; D005453:Fluorescence; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity
D001572:Benzofurans; C103650:CAM 4515; C103651:CAM 4750; D002219:Carbamates; D064729:Neurokinin-1 Receptor Antagonists