The loss of mechanical function in rat hearts subjected to either the calcium-paradox or global ischemia heart failure models was found to correlate with decreases in myocardial taurine levels. Therefore, the effect of taurine treatment was assessed in the two failure procedures. The presence of taurine protected against loss of mechanical function resulting from the calcium paradox and prevented both the large decline in sarcolemmal ATPase activities and the increase in sarcolemmal calcium binding normally associated with this model. Parallel studies on reperfused, taurine-untreated ischemic hearts showed only minor changes in these sarcolemmal functions. Taurine treatment normalized the slight increase in calcium binding associated with ischemia, but had no observable effect on recovery of mechanical function. Although taurine returns selected parameters of the sarcolemma toward normal in both models, it only improves mechanical function in the paradox model. This suggests that calcium paradox-induced heart failure is more closely associated with sarcolemmal dysfunction than ischemic heart failure.

PurposeBendamustine is a unique alkylating agent indicated for the treatment of chronic lymphocytic leukemia and rituximab-refractory, indolent B cell non-Hodgkin’s lymphoma. Despite the extensive experience with bendamustine, its pharmacokinetic profile has only recently been described. This overview summarizes the pharmacokinetics, pharmacokinetic/pharmacodynamic relationships, and drug–drug interactions of bendamustine in adult and pediatric patients with hematologic malignancies.MethodsA literature search and data on file (including a human mass balance study, pharmacokinetic population analyses in adult and pediatric patients, and modeling analyses) were evaluated for inclusion.ResultsBendamustine concentrations peak at end of intravenous infusion (~1 h). Subsequent elimination is triphasic, with the intermediate t1/2 (~40 min) as the effective t1/2 since the final phase represents <1 % of the area under the curve. Bendamustine is rapidly hydrolyzed to monohydroxy-bendamustine and dihydroxy-bendamustine, which have little or no activity. Cytochrome P450 (CYP) 1A2 oxidation yields the active metabolites γ-hydroxybendamustine and N-desmethyl-bendamustine, at low concentrations, which contribute minimally to cytotoxicity. Minor involvement of CYP1A2 in bendamustine elimination suggests a low likelihood of drug–drug interactions with CYP1A2 inhibitors. Systemic exposure to bendamustine 120 mg/m2 is comparable between adult and pediatric patients; age, race, and sex have been shown to have no significant effect on systemic exposure in either population. The effect of hepatic/renal impairment on bendamustine pharmacokinetics remains to be elucidated. Higher bendamustine concentrations may be associated with increased probability of nausea or infection. No clear exposure–efficacy response relationship has been observed.ConclusionsAltogether, the findings support dosing based on body surface area for most patient populations.

The objective of the current study was to investigate the metabolism of cytochrome P450 (CYP) probe substrates in male Sprague Dawley rat liver microsomes and to determine their substrate specificities. Time and microsomal protein concentrations were varied to determine the linear conditions for each reaction. Appropriate substrate concentrations were chosen to determine the apparent K(m) and V(max) for 17 different reactions under initial rate conditions of protein and reaction time. All reactions appeared to follow Michaelis-Menten kinetics. Subsequently, each substrate was incubated at one to two times K(m) with each of 14 baculovirus cDNA-expressed rat CYP enzymes to determine the specificity of the reaction monitored. Of the 14 enzymes tested, seven were seen as the major rat CYP enzymes responsible for the majority of the substrate metabolism tested. Testosterone 2alpha- and 16alpha-hydroxylation reactions were conducted primarily by CYP2C11, and midazolam 4-hydroxylation and triazolam 1'-hydroxylation were preferentially catalyzed by CYP3A1/2, but specificity was otherwise generally poor. The results presented herein clearly indicate that care must be taken in interpretation of metabolism results obtained in rats using standard probe substrates, especially in extrapolation of those results to humans.

Chemical structures of seven cyanide adducts of imatinib have been identified or proposed based on high-resolution MS/MS data. Mechanisms for the formation of the conjugates were also proposed. The findings may help to understand the mechanism of hepatotoxicity of imatinib in humans.

ABSTRACT:Bendamustine, a bifunctional alkylating agent, is currently in clinical trials for the treatment of hematological and other malignancies. Although it has been used in the former East Germany for more than 30 years, very limited information is available on its biotransformation. The objective of this investigation was to obtain information on the structures of metabolites excreted into rat urine and bile to understand the metabolic fate of bendamustine in vivo. Metabolites of [14 C]bendamustine hydrochloride in rat urine and bile were determined using liquid chromatography-mass spectrometry (MS) in parallel with on-line radioactivity detection in samples obtained after i.v. dosing of 3 mg/kg. A total of 17 radioactive peaks were identified in rat urine and 10 in rat bile (2 were unique to bile). Four of these metabolites had been previously reported, whereas 15 are novel. Proposed structures of all metabolites detected are based on MS n spectra generated from a linear ion trap mass spectrometer. These results suggest that the major metabolic pathways in rat are oxidative and/or hydrolytic dehalogenation, oxidation, carboxylic acid formation, N-dealkylation, sulfation, and glutathione and cysteine (probably via glutathione) conjugation. The cysteine-conjugated compounds are observed in their N-acetylated cysteine (mercapturic acid) forms.Bendamustine, a bifunctional alkylating agent ( Fig. 1), is currently in late-stage clinical trials for the treatment of hematological and other malignancies (Pönisch et al., 2006). Although it has been used in the former East Germany for more than 30 years (Teichert et al., 2005;Gandhi, 2002), limited information is available on its biotransformation. Pharmacokinetic studies in mice indicated that bendamustine concentrations in plasma rapidly decreased after i.v. dosing (Weber et al., 1991). Bendamustine metabolites excreted into rat bile and urine were investigated with 14 C-labeled compound using thin-layer chromatography analysis, and conjugated and hydroxylated metabolites were observed (Bezek et al., 1991). Hydroxylated, N-demethylated, and cysteine-conjugated metabolites of bendamustine were identified in human bile, urine, and plasma (Teichert et al., 2005), and two phase I metabolites (␥-hydroxy-and N-desmethyl-bendamustine) were further characterized by LC-MS and nuclear magnetic resonance spectroscopy after isolation from cytochrome P450 incubation mixtures (Teichert et al., 2007). Although seven metabolites were tentatively identified from the above investigations, four of which were also observed in the studies reported herein and designated M6, M16, M20, and M21 (see below), the complete metabolic fate of bendamustine in vivo remains to be fully elucidated. The other three metabolites previously observed were mono (with or without hydrolysis of the opposite chlorine)-or di-cysteine conjugates of the Nchloroethyl groups.The objective of this investigation was to obtain information on the structures of metabolites excreted into rat urine and bile to understan...