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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

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Abstract

Purpose

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.

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Abbreviations

4-BPB:

Bromophenyl boronic acid

APDISP :

Colloidal aqueous phase formed on dispersion of a SEDDS formulation

APDIGEST :

Colloidal aqueous phase formed on digestion of a SEDDS formulation

AUC:

Area under the curve

BA:

Bioavailability

BS:

Bile salt

Cmax :

Peak plasma concentration

CrEL:

Cremophor EL

CYP:

Cytochrome P450

F :

Absolute bioavailability

GI:

Gastrointestinal

HPLC:

High performance liquid chromatography

HPMC:

Hydroxypropyl methylcellulose

IV:

Intravenous

LBDDS:

Lipid-based drug delivery system

LCMS:

Liquid chromatography mass spectrometry

MC:

Medium-chain

NaTDC:

Sodium taurodeoxycholate

PL:

Phospholipid

PPI:

Polymeric precipitation inhibitors

S:

Supersaturation ratio

SBA:

Serum bile acid

SEDDS:

Self-emulsifying drug delivery system

t1/2 :

Half life

TBU:

Tributyrin units

Tmax :

Time of occurrence of peak plasma concentration

Vdβ :

Volume of distribution

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Acknowledgments and Disclosures

Funding support from the Australian Research Council (ARC) and Capsugel is gratefully acknowledged. We also thank Anya Carlson, Gail Squires, Dr. Tri-Hung Nguyen and Dr. Linda Abraham for their assistance with bioavailability studies and sample collection.

Author information

Author notes

  1. Mette U. Anby

    Present address: Technologie Servier, Orleans, France

  2. Hywel D. Williams

    Present address: Capsugel R&D, Strasbourg, France

  3. Glenn A. Edwards

    Present address: School of Animal & Veterinary Sciences, Charles Sturt University, Wagga Wagga, NSW, 2678, Australia

Authors and Affiliations

  1. Drug Delivery, Disposition and Dynamics Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria, 3052, Australia

    Mette U. Anby, Hywel D. Williams, Orlagh Feeney, Colin W. Pouton & Christopher J. H. Porter

  2. Department of Veterinary Sciences, University of Melbourne, Werribee, Victoria, 3030, Australia

    Glenn A. Edwards

  3. Capsugel R&D, Strasbourg, France

    Hassan Benameur

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  1. Mette U. Anby
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Correspondence to Christopher J. H. Porter.

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Anby, M.U., Williams, H.D., Feeney, O. et al. 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. Pharm Res 31, 1536–1552 (2014). https://doi.org/10.1007/s11095-013-1260-8

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