Effect of a lipoidic excipient on the absorption profile of compound UK 81252 in dogs after oral administration.
OBJECTIVE
Effect of caprylocaproyl macrogolglycerides (Labrasol), as a lipoidic excipient/vehicle in an oral capsule formulation, on pharmacokinetic disposition of a BCS Class 3 compound, UK-81252, was investigated in vivo in a canine model.


METHODS
The control and lipoidic formulations were administrated to six Beagle dogs in a crossover, single dose design with a 2-week washout period in between treatments. The plasma concentration-time profile for the lipoidic formulation was compared to that of the control formulation (lactose-based oral capsule).


RESULTS
Although the lipoidic formulation resulted in a markedly increased oral bioavailability (based on mean pharmacokinetic parameters, AUC(0-48 hr) and C(max) ), a double-peaking phenomenon was observed with this formulation. The most likely cause of this double-peak effect was the gastric emptying retardation attribute of the lipoidic vehicle/excipient. The initial peak (Tmax1) was due to the absorption enhancing properties of the lipoidic formulation and the second peak (Tmax2) was most likely the result of a shutdown in gastric emptying for a period of up to 2 hours (this value varied between dogs) after which the remaining Compound UK 81252 emptied from the stomach to generate the second peak.


CONCLUSIONS
Caprylocaproyl macrogolglycerides enhanced the absorption of Compound UK 81252. After oral administration, the liquid-filled formulation consistently produced a double-peak phenomenon in the plasma profile. Labrasol was determined to be the most likely culprit for this double peaking phenomenon.
Chang
Rong-Kun
RK
Shire Laboratories, Inc., Rockville, Maryland 20850, USA.
Shojaei
Amir H
AH
D000042:Absorption / Q000187:drug effects*; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D004285:Dogs; D004347:Drug Interactions; D004655:Emulsions / Q000494:pharmacology*; D005079:Excipients / Q000494:pharmacology*; D005989:Glycerides; D008698:Mesylates / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D009930:Organic Chemicals; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*
D004655:Emulsions; D005079:Excipients; D005989:Glycerides; D008698:Mesylates; D009930:Organic Chemicals; C440220:Labrasol; D014443:Tyrosine; C111998:sampatrilat