Non-linear increases in danazol exposure with dose in older vs. younger beagle dogs: the potential role of differences in bile salt concentration, thermodynamic activity, and formulation digestion.
OBJECTIVE
To explore the possibility that age-related changes in physiology may result in differences in drug bioavailability after oral administration of lipid based formulations of danazol.


METHODS
Danazol absorption from lipid formulations with increasing drug load was examined in younger (9 months) and older (8 years) beagles. Age related changes to hepatic function were assessed via changes to systemic clearance and serum bile acid concentrations. Changes to lipolytic enzyme activity and intestinal bile salt concentration were evaluated using in vitro lipolysis.


RESULTS
Drug exposure increased linearly with dose in younger animals. In older animals, bioavailability increased with increasing dose to a tipping point, beyond which bioavailability reduced (consistent with initiation of precipitation). No differences in hepatic function were apparent across cohorts. Changes to enzyme concentrations in lipolysis studies had little impact on drug precipitation/solubilisation. In contrast, higher bile salt concentrations better supported supersaturation at higher drug loads.


CONCLUSIONS
Differences in animal cohort can have a significant impact on drug absorption from lipid based formulation. For danazol, bioavailability was enhanced under some circumstances in older animals. In vitro experiments suggest that this was unlikely to reflect changes to metabolism or lipolysis, but might be explained by increases in luminal bile salt/phospholipid concentrations in older animals.
Drug Delivery, Disposition and Dynamics Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria, 3052, Australia.
Mette U
MU
Anby
Hywel D
HD
Williams
Orlagh
O
Feeney
Glenn A
GA
Edwards
Hassan
H
Benameur
Colin W
CW
Pouton
Christopher J H
CJ
Porter
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D003613:Danazol / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004285:Dogs; D004965:Estrogen Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005704:Gallbladder / Q000254:growth & development / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000254:growth & development / Q000502:physiology; D008111:Liver Function Tests; D008297:Male; D013816:Thermodynamics
D001647:Bile Acids and Salts; D004965:Estrogen Antagonists; D003613:Danazol