Infusion Rate Dependent Pharmacokinetics of Bendamustine with Altered Formation of γ-hydroxybendamustine (M3) Metabolite Following 30- and 60-min Infusion of Bendamustine in Rats.

Bendamustine is an alkylating agent administered as 1 h intravenous infusion in the clinic for the treatment of malignant haematological cancers. The aim of the study was to evaluate the pharmacokinetics of bendamustine and its key cytochrome P 450 (CYP) 1A2 mediated γ-hydroxybendamustine (M3) metabolite after 30- and 60-min intravenous infusion of bendamustine in rats. 2 groups were assigned to receive bendamustine either as 30- or 60-min infusion and doses were normalized to 15 mg/kg for the sake of statistical evaluation. Serial pharmacokinetic samples were collected and were analysed for the circulatory levels of bendamustine and its M3 metabolite. Standard pharmacokinetic parameters were generated for bendamustine and its M3 metabolite. Regardless of the intravenous regimens, Cmax coincided with end of infusion for both bendamustine and its M3 metabolite. Immediately after stoppage of infusion, a rapid decline in the plasma levels occurred for both bendamustine and M3 metabolite. The Cmax and AUC0-∞ parameters for bendamustine after 60-min infusion were 1.90 and 1.34-fold higher; while CL was lower by 1.32-fold as compared to the 30-min infusion. In contrast, the Cmax and AUC0-∞ after 30-min infusion for the M3 metabolite was 2.15- and 2.78-fold greater; while CL was 2.32-fold lower when compared to the 60-min infusion. However, T1/2 and Vz values were similar between the 2 intravenous treatments for bendamustine or the M3 metabolite. The data unequivocally confirmed the existence of differential pharmacokinetics of bendamustine and its M3 metabolite as the function of the duration of intravenous infusion.

Pharmacokinetics, tissue distribution and identification of putative metabolites of JI-101 - a novel triple kinase inhibitor in rats.

JI-101, chemically 1-[1-(2-amino-pyridin-4-ylmethyl)-1H-indol-4-yl]-3-(5-bromo-2-methoxy-phenyl)-urea hydrochloride, is a novel orally active kinase inhibitor, which has shown potent in vitro and in vivo anticancer activity against a variety of cancer cell lines and xenografts. It is currently entering Phase II clinical development for the treatment of solid tumors. The aim of the study is to assess the metabolic stability of JI-101 in various pre-clinical and human liver microsomes, to identify the major CYPs (cytochrome ß450) involved in the metabolism of JI-101 and identification of putative metabolites. We have also studied the pharmacokinetics, tissue distribution and excretion of JI-101 in Sprague Dawley rats. JI-101 was found to be stable in various liver microsomes tested. JI-101 is highly permeable and not a substrate for P-gp (permeability glycoprotein). JI-101 excreted through bile along with its mono- and di-hydroxy metabolites. Following oral administration, JI-101 was rapidly absorbed, reaching Cmax within 2 h. The t½ of JI-101 with intravenous and oral route was found to be 1.75 ± 0.79 and 2.66 ± 0.13 h, respectively. The Cl and Vd by intravenous route for JI-101 were found to be 13.0 ± 2.62 mL/min/kg and 2.11 ± 1.42 L/kg, respectively. The tissue distribution of JI-101 was extensive with rapid and preferred uptake into lung tissue. Overall, the oral bioavailability of JI-101 is 55% and the primary route of elimination for JI-101 is feces.

Altered intravenous pharmacokinetics of topotecan in rats with acute renal failure (ARF) induced by uranyl nitrate: do adenosine A1 antagonists (selective/non-selective) normalize the altered topotecan kinetics in ARF?

A series of exploratory investigations with multiple agents was carried out in normal rats and in rats with uranyl nitrate-induced acute renal failure to understand the disposition characteristics of intravenous topotecan (TPT) used as a model substrate. The disposition of TPT was unaltered in normal rats when treated with methotrexate, whereas treatment with probenecid increased the systemic exposure of TPT. In case of uranyl nitrate-induced acute renal failure (UN-ARF) rats, the systemic exposure of TPT was increased when compared with normal rats, whereas in UN-ARF rats treated with probenecid a further reduction in renal clearance of TPT was noted as compared with that of UN-ARF induced rats. Thus, TPT may be involved in the tubular secretory pathway when a passive glomerular filtration pathway for elimination was not possible. The disposition of TPT did not normalize in UN-ARF rats when treated with caffeine, a non-selective adenosine A1 receptor antagonist, whereas the selective adenosine A1 receptor antagonist (1,3-dipropyl-8-phenylxanthine, DPPX) normalized TPT pharmacokinetic disposition by improving renal function. Renal excretion studies demonstrated that CLR improved by almost fivefold following DPPX treatment in ARF rats. In addition, the qualitative stability/metabolism pattern of TPT in liver microsomes prepared from various groups of rats (normal rats, UN-ARF rats, rats treated with DPPX, and UN-ARF rats treated with DPPX) was found to be similar. In summary, using a pharmacokinetic tool as a surrogate, it has been shown that the pharmacokinetic disposition of TPT improved considerably upon treatment with DPPX, a selective adenosine A1 antagonist.