Effects of cysteine on the pharmacokinetics of intravenous adriamycin in rats with protein-calorie malnutrition.
In rats with protein-calorie malnutrition (PCM, 5% caseine diet for 4 weeks), hepatic cytochrome P450 levels suppressed markedly and cytochrome P450 mRNAs decreased significantly compared with those in control rats (23% caseine diet for 4 weeks), however, the values completely (or partially) returned to control levels by a week (from fourth week) of cysteine supplementation (rats with PCMC) (Cho, Kim et al., Arch. Biochem. Biophys. 1999, 372: 150-158). The formation of aglycone metabolites of adriamycin and adriamycinol, M3 and M4, respectively, seemed to be induced (Lee and Lee, Res. Commun. Mol. Pathol. Pharmacol. 1999, 105: 87-96) by pretreatment with dexamethasone (possibly by hepatic cytochrome P450 RL 33/cDEX, Komori and Oda, J. Biochem. 1994, 116: 114-120) in rats. Adriamycin, 16 mg/kg, was administered intravenously in 1-min to control rats and rats with PCM and PCMC. In rats with PCM, the plasma concentrations of adriamycin was higher (the area under the plasma concentration-time curve from time zero to 12 hr, AUC(0-12 hr), tended to be higher) and 24-hr urinary excretion of M3 (including its 'conjugates') seemed to increase than those in control rats, suggested that the formation of M3 was inhibited in rats with PCM. In rats with PCMC, the plasma concentrations of adriamycin were lower (the AUC(0-12 hr) was significantly smaller) and 24-hr urinary excretion of M3 (including its 'conjugates') were significantly greater than those in rats with PCM, suggested that the formation of M3 increased significantly by cysteine supplementation by restoring the enzyme system(s) that metabolize adriamycin to M3. The altered pharmacokinetic parameters of adriamycin mentioned above in rats with PCM returned to greater than those of control rats after cysteine supplementation (rats with PCMC). Above data suggested that other hepatic cytochrome P450 isozyme(s) which catalyze(s) the formation of M3 from adriamycin could be induced by cysteine supplementation.
Kim
Y G
YG
College of Pharmacy, Seoul National University, South Korea.
Cho
M K
MK
Kwon
J W
JW
Kim
S G
SG
Lee
M G
MG
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001835:Body Weight / Q000187:drug effects; D003545:Cysteine / Q000627:therapeutic use*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011502:Protein-Energy Malnutrition / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D004317:Doxorubicin; D003577:Cytochrome P-450 Enzyme System; D003545:Cysteine