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Characterization of Contents of Distal Ileum and Cecum to Which Drugs/Drug Products are Exposed During Bioavailability/Bioequivalence Studies in Healthy Adults

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Abstract

Purpose

Characterize the contents of distal ileum and cecum in healthy adults under conditions simulating the bioavailability/bioequivelance studies of drug products in fasted and fed state.

Methods

Twelve males participated in a two-phase crossover study. Phase I: subjects remained fasted overnight plus 4.5 h in the morning prior to colonoscopy. Phase II: subjects remained fasted overnight, consumed breakfast in the morning, and abstain from food until colonoscopy, 4.5 h after breakfast. Upon sampling, volume, pH and buffer capacity were measured; after ultracentrifugation, supernatant was physicochemically characterized and non-liquid particles diameter was measured.

Results

In distal ileum, pH is ~8.1 and size of non-liquid particles is ~200 μm, regardless of dosing conditions; in fed state, liquid fraction was lower whereas osmolality and carbohydrate content were higher. In cecum, the environment was similar with previously characterized environment in the ascending colon; in fasted state, size of non-liquid particles is smaller than in distal ileum (~70 μm). Fluid composition in distal ileum is different from cecum, especially in fasted state.

Conclusion

Differences in luminal environment between distal ileum and cecum may impact the performance of orally administered products which deliver drug during residence in lower intestine. Dosing conditions affect cecal environment more than in distal ileum.

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Abbreviations

AA:

Acetic acid

API:

Active pharmaceutical ingredient

BA:

n-Butyric acid

BA/BE:

Bioavailability/Bioequivalence

BIS:

Bisacodyl

C:

Cholic acid

CA:

Caproic acid

CDC:

Chenodeoxycholic acid

CHO:

Cholesterol

DC:

Deoxycholic acid

DG:

Diglyceride

FA:

Fatty acid

GC:

Glycocholic acid

GCDC:

Glycochenodeoxycholic acid

GDC:

Glycodeoxycholic acid

GI:

Gastrointestinal

HBV:

Hepatitis B virus

HCV:

Hepatitis C virus

HIV:

Human Immunodeficiency Virus

HPLC:

High performance liquid chromatography

IBA:

Iso-butyric acid

IVA:

Iso-valeric acid

LC:

Lithocholic acid

Lyso-PC:

Lyso-phosphatidylcholine

MG:

Monoglyceride

PA:

Propionic acid

PC:

Phosphatidylcholine

SCFA:

Short chain fatty acid

SD:

Standard deviation

TC:

Taurocholic acid

TCDC:

Taurochenodeoxycholic acid

TG:

Triglyceride

UDC:

Ursodeoxycholic acid

VA:

Valeric acid

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ACKNOWLEDGMENTS AND DISCLOSURES

This work would not have been possible without the participation of reliable volunteers and authors would like to express their sincere appreciation.

Authors would like to thank Ms. Maria Koursari for her excellent technical assistance during colonoscopies.

Parts of the present work have been presented as an oral presentation at the “Progress within the IMI OrBiTo project—predictive tools for oral Biopharmaceutics” meeting (Academy of Pharmaceutical Sciences, Stevenage, UK, 13 May 2014) and as a poster at AAPS Annual Meeting, November 2–6, 2014, San Diego, California, USA.

This work was performed within the OrBiTo project (http://www.orbitoproject.eu) which is funded by the Innovative Medicines Initiative Joint Undertaking under Grant Agreement No 115369.

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Authors and Affiliations

  1. Faculty of Pharmacy, School of Health Sciences, National & Kapodistrian University of Athens, Panepistimiopolis, 157 71, Zografou, Greece

    Christos Reppas, Eleni Karatza, Constantinos Markopoulos & Maria Vertzoni

  2. Red Cross Hospital of Athens, Athens, Greece

    Constantinos Goumas

Authors
  1. Christos Reppas
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  2. Eleni Karatza
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  3. Constantinos Goumas
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  4. Constantinos Markopoulos
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  5. Maria Vertzoni
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Correspondence to Maria Vertzoni.

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Reppas, C., Karatza, E., Goumas, C. et al. Characterization of Contents of Distal Ileum and Cecum to Which Drugs/Drug Products are Exposed During Bioavailability/Bioequivalence Studies in Healthy Adults. Pharm Res 32, 3338–3349 (2015). https://doi.org/10.1007/s11095-015-1710-6

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  • DOI: https://doi.org/10.1007/s11095-015-1710-6

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