Development of a radioimmunoassay for the anthrapyrazole chemotherapy agent CI-937 and the pharmacokinetics of CI-937 in rats.
The anthracyclines daunorubicin and doxorubicin are cancer chemotherapy agents that complex DNA and are widely utilized clinically. Cumulative cardiotoxicity, however, limits their prolonged use. The novel anthrapyrazole agent, CI-937, which has shown exceptional in vivo anticancer activity and reduced cardiotoxicity in preclinical models has been developed at the Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co. Due to an inability to extract CI-937 reproducibly from biological fluids, high-performance liquid chromatography is not a feasible analytical method. We developed a radioimmunoassay by conjugating CI-937 to porcine thyroglobulin to elicit rabbit antibody which was used with a radioiodinated derivative. The assay was validated for rat plasma using 50 microliters of sample with a resulting limit of quantitation of 100 pg/ml. By dilution of samples the assay can quantitate CI-937 levels up to 16 micrograms/ml. The antiserum is very specific as evidenced by cross-reactivities of less than 0.4% for structural analogues and less than 0.004% for any of the commonly used cancer chemotherapy agents. Analysis of plasma samples from rats treated with a single 5 mg/kg i.v. dose indicated that CI-937 is rapidly cleared from plasma and is extensively bound to tissues.
Department of Pharmacokinetics and Drug Metabolism, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
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Nordblom
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Pachla
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Chang
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Whitfield
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Showalter
D000818:Animals; D000880:Anthraquinones / Q000032:analysis* / Q000097:blood / Q000493:pharmacokinetics; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000032:analysis* / Q000097:blood; D055598:Chemical Phenomena; D002621:Chemistry; D003429:Cross Reactions; D005260:Female; D008297:Male; D011720:Pyrazoles / Q000032:analysis* / Q000097:blood / Q000493:pharmacokinetics; D011817:Rabbits; D011863:Radioimmunoassay / Q000379:methods*; D051381:Rats
D000880:Anthraquinones; D000970:Antineoplastic Agents; D011720:Pyrazoles; C046658:teloxantrone