Pharmacokinetics and tissue distribution of cryptophycin 52 (C-52) epoxide and cryptophycin 55 (C-55) chlorohydrin in mice with subcutaneous tumors

• Published in: Cancer chemotherapy and pharmacology 2003-07, Vol.52 (1), p.25-33
• Main Authors: BOINPALLY, Ramesh R, POLIN, Lisa, ZHOU, Sen-Lin, JASTI, Bhaskara R, WIEGAND, Richard A, WHITE, Kathryn, KUSHNER, Juiwanna, HORWITZ, Jerome P, CORBETT, Thomas H, PARCHMENT, Ralph E
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Area Under Curve; Biological and medical sciences; Chemotherapy; Depsipeptides; Disease Models, Animal; Female; Half-Life; Humans; Lactams - pharmacokinetics; Lactams - therapeutic use; Lactones - pharmacokinetics; Lactones - therapeutic use; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - metabolism; Medical sciences; Metabolic Clearance Rate; Mice; Peptides, Cyclic - pharmacokinetics; Peptides, Cyclic - therapeutic use; Pharmacology. Drug treatments; Tissue Distribution; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - metabolism
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-003-0621-0

To compare the pharmacokinetics and tissue distribution (both normal and tumor) of cryptophycin 52 (C-52) and its putative chlorohydrin prodrug cryptophycin 55 (C-55) in a murine model and to investigate a possible mechanism behind the superior activity of C-55. Mammary adenocarcinoma 16/c tumor-bearing mice were treated with an i.v. bolus of 11 mg/kg C-52 or 38 mg/kg C-55 in Cremophor-alcohol. At predetermined time intervals, C-52 and C-55 concentrations in plasma, liver, kidney, small intestine and tumors were measured using a previously described HPLC method. Pharmacokinetic parameters were computed using noncompartmental methods. Tissue (both normal and tumor) to plasma ratios as a function of time were also calculated for comparison. Both C-52 and C-55 were rapidly distributed into different tissues including tumors following i.v. administration. However, the affinities of these compounds towards different tissues were different. Thus, the half-lives (minutes) of C-55 were in the decreasing order liver (725), intestine (494), tumor (206), kidney (62) and plasma (44), whereas the AUC values (microg x min/ml) were in the order tumor (9077), liver (7734), kidney (6790), plasma (2372) and intestine (2234). For C-52, the half-lives (minutes) were in the decreasing order liver (1333), kidney (718), intestine (389), tumor (181) and plasma (35), and the AUC values (microg x min/ml) were in the order kidney (1164), liver (609), intestine (487), plasma (457) and tumor (442). The relative exposures to C-52 after i.v. injection of C-55 were plasma 3.9%, tumor 80.8%, kidney 3.4%, liver 1.1% and intestine 2.8%. Although plasma exposure to C-52 following C-55 administration was relatively small, the use of C-55 to deliver C-52 increased the retention of C-52 and its AUC in tumor compared to direct injection of C-52. Simultaneously, this approach shortened C-52 retention in all normal tissues studied. The distribution of C-55 and its bioconversion to C-52 in different organs and tumor tissue observed in this study suggest the ability of C-55 to target tumor tissue, creating a depot of C-52 in tumor. Increased C-52 exposure of tumor, with concomitant decreased exposure of normal tissue, is a contributing factor to the superior activity of C-55 versus C-52. However, except in the case of tumor tissue in which 81% of C-55 converts to C-52, only a minor amount of C-55 may serve as a prodrug for C-52, whereas the majority is handled by the biosystem through a different ro