Metabolism of the cardioprotective agents dexrazoxane (ICRF-187) and levrazoxane (ICRF-186) by the isolated hepatocyte

Abstract

1. The metabolism of dexrazoxane (ICRF-187) and its optical isomer levrazoxane (ICRF-186) by the isolated rat hepatocyte was studied by hplc. 2. 4-Chlorobenzenesulphonamide, which is a strong inhibitor of dihydropyrimidine amidohydrolase (DHPase), caused 82% inhibition of the loss of dexrazoxane from the hepatocyte suspension. 3. Dexrazoxane was metabolized at an initial rate by isolated hepatocytes that was 1.8 times faster than levrazoxane. This ratio is close to that found for purified DHPase, suggesting that DHPase present in the hepatocyte catalyses the ring-opening hydrolysis of these drugs. 4. The ratios of the rates at which each of the one-ring open intermediates of dexrazoxane and levrazoxane were produced in the hepatocyte suspension are also consistent with DHPase being primarily responsible for the metabolism of dexrazoxane and levrazoxane. 5. Thus, the DHPase-catalysed formation of the one-ring opened intermediates enhances the rate at which the presumably active metal-ion binding forms of dexrazoxane are produced in the hepatocyte. 6. The DHPase content of the hepatocyte was estimated to be 1.2 nmol/kg of total hepatocyte mass, or equivalently 5700 molecules of DHPase per hepatocyte.

The Metabolites of the Cardioprotective Drug Dexrazoxane Do Not Protect Myocytes from Doxorubicin-Induced Cytotoxicity

“…We previously showed in isolated hepatocytes (Hasinoff et al, 1994), in a rat model , and in humans (Schroeder et al, 2003) that dexrazoxane was rapidly metabolized to the one-ring open compounds B and C, and ADR-925 (Fig. 1).…”

“…ADR-925 may then either remove iron from the iron-doxorubicin complex (Buss and Hasinoff, 1993) (Huang et al, 1982;Diop et al, 2000). Thus, dexrazoxane, which is easily permeable to cells (Dawson, 1975), can be considered a neutral prodrug analog of EDTA.We previously showed in isolated hepatocytes (Hasinoff et al, 1994), in a rat model , and in humans (Schroeder et al, 2003) that dexrazoxane was rapidly metabolized to the one-ring open compounds B and C, and ADR-925 (Fig. 1).…”

Metabolism of the One-Ring Open Metabolites of the Cardioprotective Drug Dexrazoxane to Its Active Metal-Chelating Form in the Rat

“…We also previously showed that DHPase, which is present in the liver and the kidney, can efficiently hydrolyze dexrazoxane (Hasinoff et al, 1991(Hasinoff et al, , 1994Hasinoff, 1993Hasinoff, , 1994cHasinoff and Aoyama, 1999b) and is likely the enzyme that is primarily responsible for the metabolism of dexrazoxane to B and C. We have also shown that DHPase is unable to convert B and C into ADR-925 (Hasinoff et al, 1991). Likewise, we have shown that DHOase is able to enzymatically hydrolyze B and C to ADR-925 but is unable to hydrolyze dexrazoxane .…”

“…It is, however, observed that in both humans and rats , dexrazoxane is quickly metabolized to B and C, and then to ADR-925. The rapid rate of hydrolysis of dexrazoxane to B and C and the rapid appearance of ADR-925 in plasma in vivo suggested that, first, dexrazoxane and, then, B and C were all enzymatically metabolized.We previously showed that the dexrazoxane metabolic intermediates B and C are rapidly formed from dexrazoxane in a primary rat hepatocyte suspension (Hasinoff et al, 1994), a result that is consistent with dexrazoxane being metabolized by the zinc hydrolase DHPase (EC 3.5.2.2). However, although pure DHPase enzymatically hydrolyzes dexrazoxane to B and C, it is unable to enzymatically hydrolyze B and C to ADR-925 (Hasinoff et al, 1991;Hasinoff, 1993).…”

“…We previously showed that the dexrazoxane metabolic intermediates B and C are rapidly formed from dexrazoxane in a primary rat hepatocyte suspension (Hasinoff et al, 1994), a result that is consistent with dexrazoxane being metabolized by the zinc hydrolase DHPase (EC 3.5.2.2). However, although pure DHPase enzymatically hydrolyzes dexrazoxane to B and C, it is unable to enzymatically hydrolyze B and C to ADR-925 (Hasinoff et al, 1991;Hasinoff, 1993).…”