Lipid-based delivery systems for improving the bioavailability and lymphatic transport of a poorly water-soluble LTB4 inhibitor.
Ontazolast is a potent inhibitor (IC50 = 1 nm) of calcium ionophore A23187-stimulated leukotriene B4 (LTB4) biosynthesis in human peripheral blood leukocytes. The compound is practically insoluble in water (0.14 microgram/mL) and previous studies in animals have demonstrated extensive presystemic drug clearance through hepatic first-pass metabolism. Bioavailability of a suspension formulation in rats was less than 1%, but increased to approximately 9% when administered as a 20% soybean oil-in-water emulsion. The emulsion formulation and three additional lipid-based formulations were administered by gavage to conscious, minimally restrained rats in a novel, double-cannulated model to determine the effects of formulation on systemic blood absorption and mesenteric lymph transport of ontazolast. The bioavailability of ontazolast was significantly and substantially enhanced by all of the lipid-based formulations. While these formulations also significantly increased the amount of ontazolast transported by the lymph, the total amounts transported were insufficient to account for the improvement in bioavailability, which may be due to the elimination or reduction of the barriers of poor aqueous solubility and slow dissolution to absorption of ontazolast from the gastrointestinal tract, or the effects of lipid on the gastrointestinal membrane permeability, transit time, or metabolism of ontazolast. Semisolid SEDDS formulations, composed of Peceol and Gelucire 44/14, produced bioavailability similar to the emulsion formulation. The total amount of ontazolast transported by the lymph varied directly with the amount of concurrent triglyceride transport and appeared to be favored by formulations that prolong gastric emptying time or promote rapid absorption of ontazolast from the gastrointestinal tract.
Hauss
D J
DJ
Department of Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877-0368, USA. DHauss@BI-Pharm.com
Fogal
S E
SE
Ficorilli
J V
JV
Price
C A
CA
Roy
T
T
Jayaraj
A A
AA
Keirns
J J
JJ
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D001583:Benzoxazoles / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D002914:Chylomicrons / Q000737:chemistry; D004337:Drug Carriers; D004655:Emulsions / Q000493:pharmacokinetics; D005079:Excipients / Q000737:chemistry; D005989:Glycerides / Q000737:chemistry; D006207:Half-Life; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000502:physiology; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D008208:Lymphatic System / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012995:Solubility; D013024:Soybean Oil / Q000737:chemistry; D013535:Suspensions / Q000493:pharmacokinetics; D014280:Triglycerides / Q000378:metabolism*
D001583:Benzoxazoles; D002914:Chylomicrons; D004337:Drug Carriers; D004655:Emulsions; D005079:Excipients; D005989:Glycerides; D013535:Suspensions; D014280:Triglycerides; D007975:Leukotriene B4; D013024:Soybean Oil; C090950:ontazolast; C005953:monoolein