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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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 route of elimination. Tissue distribution combined with rate of conversion may be an important determinant of the relative effectiveness of other epoxide-chlorohydrin pairs of cryptophycins.
The Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA.
Ramesh R
RR
Boinpally
Lisa
L
Polin
Sen-Lin
SL
Zhou
Bhaskara R
BR
Jasti
Richard A
RA
Wiegand
Kathryn
K
White
Juiwanna
J
Kushner
Jerome P
JP
Horwitz
Thomas H
TH
Corbett
Ralph E
RE
Parchment
D000818:Animals; D019540:Area Under Curve; D047630:Depsipeptides; D004195:Disease Models, Animal; D005260:Female; D006207:Half-Life; D006801:Humans; D007769:Lactams / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007783:Lactones / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D008657:Metabolic Clearance Rate; D051379:Mice; D010456:Peptides, Cyclic / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D047630:Depsipeptides; D007769:Lactams; D007783:Lactones; D010456:Peptides, Cyclic; C413424:cryptophycin 55; C114033:cryptophycin 52