Bioavailability and pharmacokinetics of the cardioprotecting flavonoid 7-monohydroxyethylrutoside in mice

Abstract

Purpose

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 μmol.min.ml⁻¹ and 4.9±1.3 μmol.min.g⁻¹ wet tissue, respectively. After i.p. administration, a mean peak plasma concentration of about 130 μM monoHER was maintained from 5 to 15 min after administration. The AUC_0–120 min values of monoHER were 6.1±1.1 μmol.min.ml⁻¹ and 1.6±0.4 μmol.min.g⁻¹ wet tissue in plasma and heart tissue, respectively. After s.c. administration, monoHER levels in plasma reached a maximum (about 230 μM) 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 μmol.min.ml⁻¹, 2.0±0.1, 22.4±2.0 and 20.5±5.7 μmol.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 C_max was 131 μM and the AUC_∞ was 6.3 μM.min. These values will be considered endpoints for the clinical phase I study of monoHER.