Biotransformation of topotecan in the isolated perfused rat liver: identification of three novel metabolites.
This study evaluates the metabolism of the anticancer drug topotecan (TPT) in the isolated perfused rat liver of male Wistar-rats. Using a sensitive high-performance liquid chromatography method, in bile TPT, its ring-opened hydroxycarboxylate form and three new metabolites could be quantified. Enzymatic hydrolysis of the metabolites with beta-glucuronidase and mass spectroscopy revealed the existence of glucuronidated TPT as well as unconjugated and glucuronidated bidesmethyl TPT. Biliary secretion of glucuronidated N-bidesmethyl TPT was fast reaching a maximum already after 15 min(30.6 +/- 15.1 pmol/g liver.min), whereas secretion of TPT, topotecan glucuronide and N-bidesmethyl TPT was delayed (maximum at 30 min: 431 +/- 19, 6.4 +/- 2.1 and 12.7 +/- 2.7 pmol/g liver.min, respectively). No release of TPT metabolites into the perfusate was detected. The amount of TPT, TPT glucuronide, N-bidesmethyl TPT and N-bidesmethyl TPT glucuronide excreted into bile during 60 min of perfusion was 2.10 +/- 0.483%, 0.031 +/- 0.006%, 0.058 +/- 0.013% and 0.108 +/- 0.012% of TPT cleared from the perfusate over 60 min, respectively. In conclusion we could identify three novel TPT metabolites, however, their overall metabolism in the rat liver is low.
Platzer
P
P
Institute of Pharmaceutical Chemistry, University of Vienna, Austria.
Schaden
S
S
Thalhammer
T
T
Hamilton
G
G
Rosenberg
B
B
Silgoner
I
I
Jäger
W
W
D000818:Animals; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005965:Glucuronates / Q000032:analysis; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D015394:Molecular Structure; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D013997:Time Factors; D019772:Topotecan / Q000493:pharmacokinetics*
D005965:Glucuronates; D019772:Topotecan