Effect of ingested lipids on drug dissolution and release with concurrent digestion: a modeling approach.
OBJECTIVE
To mechanistically study and model the effect of lipids, either from food or self-emulsifying drug delivery systems (SEDDS), on drug transport in the intestinal lumen.


METHODS
Simultaneous lipid digestion, dissolution/release, and drug partitioning were experimentally studied and modeled for two dosing scenarios: solid drug with a food-associated lipid (soybean oil) and drug solubilized in amodel SEDDS (soybean oil and Tween 80 at 1:1 ratio). Rate constants for digestion, permeability of emulsion droplets, and partition coefficients in micellar and oil phases were measured, and used to numerically solve the developed model.


RESULTS
Strong influence of lipid digestion on drug release from SEDDS and solid drug dissolution into food-associated lipid emulsion was observed and predicted by the developed model. Ninety minutes after introduction of SEDDS, there was 9% and 70% drug release in the absence and presence of digestion, respectively. However, overall drug dissolution in the presence of food-associated lipids occurred over a longer period than without digestion.


CONCLUSIONS
A systems-based mechanistic model incorporating simultaneous dynamic processes occurring upon dosing of drug with lipids enabled prediction of aqueous drug concentration profile. This model, once incorporated with a pharmacokinetic model considering processes of drug absorption and drug lymphatic transport in the presence of lipids, could be highly useful for quantitative prediction of impact of lipids on bioavailability of drugs.
Fulden
F
Buyukozturk
Selena
S
Di Maio
David E
DE
Budil
Rebecca L
RL
Carrier
D003198:Computer Simulation; D004063:Digestion; D004337:Drug Carriers / Q000378:metabolism*; D004435:Eating; D004655:Emulsions / Q000378:metabolism*; D006801:Humans; D008066:Lipolysis; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry; D010599:Pharmacokinetics; D012995:Solubility; D013024:Soybean Oil / Q000378:metabolism*
D004337:Drug Carriers; D004655:Emulsions; D004364:Pharmaceutical Preparations; D013024:Soybean Oil