Stereoselective metabolism of dexrazoxane (ICRF-187) and levrazoxane (ICRF-186)

Hasinoff, Brian B.; Aoyama, Ronald G.

doi:10.1002/(sici)1520-636x(1999)11:4<286::aid-chir5>3.0.co;2-5

Cited by 13 publications

(3 citation statements)

References 18 publications

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“…The supposition that dexrazoxane was a metabolic perturbant was substantiated in the 2.5-h studies, which showed that administration of this compound alone altered protein synthesis, although this effect was not apparent in 24-h treated rats. The pharmacokinetics of dexrazoxane in the rat have been published and its short half-life and rapid elimination (14,22) may help to explain why at 24 h, we see no signi cant effect of dexrazoxane alone on any of the protein synthesis parameters, whereas at 2.5-h study, it increases C s , k s , and k RNA .…”

Section: Discussionmentioning

confidence: 89%

“…We hypothesised that dexrazoxane would alter hepatic protein synthesis, perhaps because of its chelating properties (37). The ring ring-opening hydrolysis of the chirally structured dexrazoxane, by the enzyme dihydropyrimidine amidohydrolase, occurs in the liver (14). The hydrolysis product of ICRF-159 (ie, DL-N,N -dicarboxamidomethyl-N,Ndiacarboxymethyl-1,2-diamino propane; ICRF-198, ADR-925) has an EDTA structure and chelates metals such as copper, iron, and zinc, which may alter normal homeostatic mechanisms (57).…”

Section: Discussionmentioning

confidence: 99%

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Acute Dosage With Dexrazoxane, but not Doxorubicin, Is Associated With Increased Rates of Hepatic Protein Synthesis in vivo

et al. 2001

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An investigation was carried out into the effects of dexrazoxane and doxorubicin on hepatic protein synthesis in vivo. The protocol included 8 groups of rats and involved a pretreatment stage of 30 min followed by a treatment stage of either 2.5 or 24 h. Male Wistar rats ( 0.15-0.20 kg) were pretreated with either dexrazoxan e (100 mg/kg; 5 ml/kg) or saline (0.15 mol/l NaCl; 5 ml/kg). At 30 min after the pretreatment , rats were again injected with either doxorubicin (5 mg/kg; 10 ml/kg) or saline (0.15 mol/l NaCl; 10 ml/kg) in the treatment phase. Rats were sacri ced at either 2.5 or 24 h after the last doxorubicin or saline injection. Rate of protein synthesis were measured 10 min prior to sacri cing rats, with a ooding dose of L-[4-3 H]phenylalanine . Liver was analyzed for the protein synthetic capacity (C s , mg RNA/g protein), the fractional rate of protein synthesis (k s , %/d), and the RNA activity (k RNA mg protein/d/mg RNA). Complementary analysis included plasma albumin, total protein and activities of alkaline phosphatase , and aspartate aminotransferase . In the 2.5-h study, doxorubici n alone had no effect on any of the above variables. Dexrazoxane alone increased C s , k s and k RNA at 2.5 h. Combined dexrazoxan e doxorubicin increased hepatic C S and k s with concomitant reductions in total plasma protein. In the 24-h study, doxorubicin alone had no effect on any of the variables. Dexrazoxan e alone had no effect on either C S , k s , or k RNA but raised plasma activities of alkaline phosphatas e and aspartate aminotransferase. Combined dexrazoxan e doxorubicin increased C s and k s and decreased total plasma protein and increased plasma aspartate aminotransferas e activities at 24 h. In conclusion, there is no evidence that acutely doxorubicin per se has measurable effects on hepatic protein synthesis in vivo in an acute period. However, acutely dexrazoxan e increases hepatic protein synthesis, which may represent its putative cytotoxic effects, as indicated by raised serum activities of liver enzymes. A combination of both dexrazoxane doxorubici n appears to have a greater effect in increasing liver protein synthesis than dexrazoxan e alone.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Acute Dosage With Dexrazoxane, but not Doxorubicin, Is Associated With Increased Rates of Hepatic Protein Synthesis in vivo

et al. 2001

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“…3.6) as an enzyme with clear specificity for cyclic imides (ÀCOÀNRÀCOÀ ) and cyclic ureides (ÀCOÀNHÀCOÀNHÀ ). An example of a six-membered cyclic imide is that of (þ)-(S)-dexrazoxane (3.164), a compound shown to protect against doxorubicininduced cardiotoxicity which acts probably by diffusing into cells and hydrolyzing to its rings-opened, metal-chelating metabolites 3.165, 3.166, and 3.167 [129]. Chemical hydrolysis of dexrazoxane under physiological conditions was slow with half-lives of several hours.…”

Section: Fig 332 Thismentioning

confidence: 99%

The Biochemistry of Drug Metabolism — An Introduction. Part 3. Reactions of Hydrolysis and Their Enzymes

Testa

Kraemer

2007

ChemInform

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The Biochemistry of Drug Metabolism – An Introduction

Testa

Krämer

2007

Chemistry & Biodiversity

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This review continues a general presentation of the metabolism of drugs and other xenobiotics begun in two recent issues of Chemistry & Biodiversity. This Part presents some of the numerous hydrolases involved, their nomenclature, relevant biochemical properties, catalytic mechanisms, and the many reactions of hydrolysis they catalyze. A number of medicinally, environmentally, and toxicologically relevant examples are presented and discussed. The reactions examined include the hydrolysis of carboxylic esters, amides and peptides, lactones, and other labile rings, and esters of inorganic acids. The hydration of epoxides and its enzymology are treated separately.

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Stereoselective metabolism of dexrazoxane (ICRF-187) and levrazoxane (ICRF-186)

Cited by 13 publications

References 18 publications

Acute Dosage With Dexrazoxane, but not Doxorubicin, Is Associated With Increased Rates of Hepatic Protein Synthesis in vivo

Acute Dosage With Dexrazoxane, but not Doxorubicin, Is Associated With Increased Rates of Hepatic Protein Synthesis in vivo

The Biochemistry of Drug Metabolism — An Introduction. Part 3. Reactions of Hydrolysis and Their Enzymes

The Biochemistry of Drug Metabolism – An Introduction

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