Bioavailability and pharmacokinetics of the cardioprotecting flavonoid 7-monohydroxyethylrutoside in mice.
OBJECTIVE
The pharmacokinetics and bioavailability of monoHER, a promising protector against doxorubicin-induced cardiotoxicity, were determined after different routes of administration.


METHODS
Mice were treated with 500 mg.kg(-1) monoHER intraperitoneally (i.p.), subcutaneously (s.c.) or intravenously (i.v.) or with 1000 mg.kg(-1) orally. Heart tissue and plasma were collected 24 h after administration. In addition liver and kidney tissues were collected after s.c. administration. The levels of monoHER were measured by HPLC with electrochemical detection.


RESULTS
After i.v. administration the AUC(0-120 min) values of monoHER in plasma and heart tissue were 20.5+/-5.3 micromol.min.ml(-1) and 4.9+/-1.3 micromol.min.g(-1) wet tissue, respectively. After i.p. administration, a mean peak plasma concentration of about 130 microM monoHER was maintained from 5 to 15 min after administration. The AUC(0-120 min) values of monoHER were 6.1+/-1.1 micromol.min.ml(-1) and 1.6+/-0.4 micromol.min.g(-1) wet tissue in plasma and heart tissue, respectively. After s.c. administration, monoHER levels in plasma reached a maximum (about 230 microM) between 10 and 20 min after administration. The AUC(0-120 min) values of monoHER in plasma, heart, liver and kidney tissues were 8.0+/-0.6 micromol.min.ml(-1), 2.0+/-0.1, 22.4+/-2.0 and 20.5+/-5.7 micromol.min.g(-1), respectively. The i.p. and s.c. bioavailabilities were about 30% and 40%, respectively. After oral administration, monoHER could not be detected in plasma, indicating that monoHER had a very poor oral bioavailability.


CONCLUSIONS
MonoHER was amply taken up by the drug elimination organs liver and kidney and less by the target organ heart. Under cardioprotective conditions (500 mg/kg, i.p.), the Cmax was 131 microM and the AUC(infinity) was 6.3 microM.min. These values will be considered endpoints for the clinical phase I study of monoHER.
Abou El Hassan
Mohamed A I
MA
Clinical Research Laboratory of Medical Oncology, Department of Medical Oncology, Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Kedde
Marc A
MA
Zwiers
Ursula T H
UT
Tourn
E
E
Haenen
Guido R M M
GR
Bast
Aalt
A
van der Vijgh
Wim J F
WJ
D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D006896:Hydroxyethylrutoside / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000378:metabolism
D006896:Hydroxyethylrutoside