Improved lipid lowering activity of bezafibrate following continuous gastrointestinal administration: pharmacodynamic rationale for sustained release preparation of the drug.
OBJECTIVE
To evaluate the role of different routes and modes of administration of bezafibrate (BZF) on its hypolipidemic activity. We hypothesize that the major sites of BZF action are located presystemically as in other "gastrointestinal (GI) drugs." Thus, continuous administration of the drug to the GI tract is expected to augment its efficacy and provides a rationale for an oral sustained release preparation of the drug.


METHODS
The hypothesis was investigated in three experimentally induced-hyperlipidemia rat models. Models A and B were based on cholesterol-enriched diets and Model C on induced acute hyperlipidemia by triton 225 mg/kg. The pharmacokinetics and the pharmacodynamics of the drug following various modes of administration were examined.


RESULTS
In all cases, continuous administration of the drug into the duodenum (IGI) at a dose of 30 mg/kg/day for 3 days (Models A and B) or over 18 hr (Model C) reduced significantly both total cholesterol and triglycerides levels and elevated HDL cholesterol levels in comparison to bolus oral administration of the same dose, as well as in comparison to equivalent intravenous infusion (Model C). Infusion of the drug directly into the portal vein produced an equivalent activity to IGI administration. The pharmacokinetic study showed 100% oral bioavailability, good colonic absorption properties and an indication for an enterohepatic cycle.


CONCLUSIONS
The results confirm that BZF has a first pass hepatic pharmacodynamic effect. Administration of BZF in a slow release matrix tablet to the rats produced the same magnitude of effect as IGI administration, thus proving the pharmacodynamic rationale for this mode of administration for GI drugs.
Hoffman
A
A
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel. ahoffman@cc.huji.ac.il
Lomnicky
Y
Y
Luria
M H
MH
Gilhar
D
D
Friedman
M
M
D000818:Animals; D001629:Bezafibrate / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D008076:Cholesterol, HDL / Q000097:blood; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D004386:Duodenum; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008049:Lipase / Q000037:antagonists & inhibitors; D008055:Lipids / Q000097:blood*; D008075:Lipoproteins, HDL / Q000097:blood; D008297:Male; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013501:Surface-Active Agents / Q000494:pharmacology
D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D003692:Delayed-Action Preparations; D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D008055:Lipids; D008075:Lipoproteins, HDL; D013501:Surface-Active Agents; D011092:Polyethylene Glycols; D002784:Cholesterol; D008049:Lipase; C016811:tyloxapol; D001629:Bezafibrate