Mechanistic understanding of time-dependent oral absorption based on gastric motor activity in humans

Kazutaka Higaki, Sally Y. Choe, Raimar Löbenberg, Lynda S. Welage, Gordon L. Amidon

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

The relationship of gastric motor activity and gastric emptying of 0.7 mm caffeine pellets with their absorption was investigated in the fed state in healthy human subjects by simultaneous monitoring of antral motility and plasma concentrations. A kinetic model for gastric emptying-dependent absorption yielded multiple phases of gastric emptying and rate constants (kg) with large inter-individual differences and large variability in onset of gastric emptying (50-175 min). The model suggests that 50% of the dose is emptied in 1-2 h and over 90% emptied by 3.5 h following dosing, in all subjects. The maximum values of kg (kg(max)) were much greater than those reported for emptying of liquids in the fasted state and were comparable to kg values in the late Phase II/III of the migrating motor complex (MMC). The model described the observed irregular absorption rate-time and plasma concentration-time profiles adequately but not in detail. The model was more successful at simulating double-peak phenomena in absorption rate profiles and onset of caffeine absorption. The results suggest that gastric emptying regulates drug absorption of small particles in the fed state. Further, estimates of ka derived using the time-dependent absorption model were closer to the intrinsic absorption rate constant for caffeine.

Original languageEnglish
Pages (from-to)313-325
Number of pages13
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Volume70
Issue number1
DOIs
Publication statusPublished - Sep 2008
Externally publishedYes

Fingerprint

Stomach
Motor Activity
Gastric Emptying
Caffeine
Migrating Myoelectric Complexes
Individuality
Healthy Volunteers
Pharmaceutical Preparations

Keywords

  • Absorption rate
  • Absorption rate constant
  • Caffeine
  • Fed state
  • Gastric emptying
  • Gastric motor activity
  • Plasma concentration-time profile
  • Time-dependent absorption

ASJC Scopus subject areas

  • Biotechnology
  • Pharmaceutical Science

Cite this

Mechanistic understanding of time-dependent oral absorption based on gastric motor activity in humans. / Higaki, Kazutaka; Choe, Sally Y.; Löbenberg, Raimar; Welage, Lynda S.; Amidon, Gordon L.

In: European Journal of Pharmaceutics and Biopharmaceutics, Vol. 70, No. 1, 09.2008, p. 313-325.

Research output: Contribution to journalArticle

Higaki, Kazutaka ; Choe, Sally Y. ; Löbenberg, Raimar ; Welage, Lynda S. ; Amidon, Gordon L. / Mechanistic understanding of time-dependent oral absorption based on gastric motor activity in humans. In: European Journal of Pharmaceutics and Biopharmaceutics. 2008 ; Vol. 70, No. 1. pp. 313-325.
@article{6fff05bcb0014f3a87dc7c39461e9fa7,
title = "Mechanistic understanding of time-dependent oral absorption based on gastric motor activity in humans",
abstract = "The relationship of gastric motor activity and gastric emptying of 0.7 mm caffeine pellets with their absorption was investigated in the fed state in healthy human subjects by simultaneous monitoring of antral motility and plasma concentrations. A kinetic model for gastric emptying-dependent absorption yielded multiple phases of gastric emptying and rate constants (kg) with large inter-individual differences and large variability in onset of gastric emptying (50-175 min). The model suggests that 50{\%} of the dose is emptied in 1-2 h and over 90{\%} emptied by 3.5 h following dosing, in all subjects. The maximum values of kg (kg(max)) were much greater than those reported for emptying of liquids in the fasted state and were comparable to kg values in the late Phase II/III of the migrating motor complex (MMC). The model described the observed irregular absorption rate-time and plasma concentration-time profiles adequately but not in detail. The model was more successful at simulating double-peak phenomena in absorption rate profiles and onset of caffeine absorption. The results suggest that gastric emptying regulates drug absorption of small particles in the fed state. Further, estimates of ka derived using the time-dependent absorption model were closer to the intrinsic absorption rate constant for caffeine.",
keywords = "Absorption rate, Absorption rate constant, Caffeine, Fed state, Gastric emptying, Gastric motor activity, Plasma concentration-time profile, Time-dependent absorption",
author = "Kazutaka Higaki and Choe, {Sally Y.} and Raimar L{\"o}benberg and Welage, {Lynda S.} and Amidon, {Gordon L.}",
year = "2008",
month = "9",
doi = "10.1016/j.ejpb.2008.02.022",
language = "English",
volume = "70",
pages = "313--325",
journal = "European Journal of Pharmaceutics and Biopharmaceutics",
issn = "0939-6411",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - Mechanistic understanding of time-dependent oral absorption based on gastric motor activity in humans

AU - Higaki, Kazutaka

AU - Choe, Sally Y.

AU - Löbenberg, Raimar

AU - Welage, Lynda S.

AU - Amidon, Gordon L.

PY - 2008/9

Y1 - 2008/9

N2 - The relationship of gastric motor activity and gastric emptying of 0.7 mm caffeine pellets with their absorption was investigated in the fed state in healthy human subjects by simultaneous monitoring of antral motility and plasma concentrations. A kinetic model for gastric emptying-dependent absorption yielded multiple phases of gastric emptying and rate constants (kg) with large inter-individual differences and large variability in onset of gastric emptying (50-175 min). The model suggests that 50% of the dose is emptied in 1-2 h and over 90% emptied by 3.5 h following dosing, in all subjects. The maximum values of kg (kg(max)) were much greater than those reported for emptying of liquids in the fasted state and were comparable to kg values in the late Phase II/III of the migrating motor complex (MMC). The model described the observed irregular absorption rate-time and plasma concentration-time profiles adequately but not in detail. The model was more successful at simulating double-peak phenomena in absorption rate profiles and onset of caffeine absorption. The results suggest that gastric emptying regulates drug absorption of small particles in the fed state. Further, estimates of ka derived using the time-dependent absorption model were closer to the intrinsic absorption rate constant for caffeine.

AB - The relationship of gastric motor activity and gastric emptying of 0.7 mm caffeine pellets with their absorption was investigated in the fed state in healthy human subjects by simultaneous monitoring of antral motility and plasma concentrations. A kinetic model for gastric emptying-dependent absorption yielded multiple phases of gastric emptying and rate constants (kg) with large inter-individual differences and large variability in onset of gastric emptying (50-175 min). The model suggests that 50% of the dose is emptied in 1-2 h and over 90% emptied by 3.5 h following dosing, in all subjects. The maximum values of kg (kg(max)) were much greater than those reported for emptying of liquids in the fasted state and were comparable to kg values in the late Phase II/III of the migrating motor complex (MMC). The model described the observed irregular absorption rate-time and plasma concentration-time profiles adequately but not in detail. The model was more successful at simulating double-peak phenomena in absorption rate profiles and onset of caffeine absorption. The results suggest that gastric emptying regulates drug absorption of small particles in the fed state. Further, estimates of ka derived using the time-dependent absorption model were closer to the intrinsic absorption rate constant for caffeine.

KW - Absorption rate

KW - Absorption rate constant

KW - Caffeine

KW - Fed state

KW - Gastric emptying

KW - Gastric motor activity

KW - Plasma concentration-time profile

KW - Time-dependent absorption

UR - http://www.scopus.com/inward/record.url?scp=50149090855&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=50149090855&partnerID=8YFLogxK

U2 - 10.1016/j.ejpb.2008.02.022

DO - 10.1016/j.ejpb.2008.02.022

M3 - Article

C2 - 18434110

AN - SCOPUS:50149090855

VL - 70

SP - 313

EP - 325

JO - European Journal of Pharmaceutics and Biopharmaceutics

JF - European Journal of Pharmaceutics and Biopharmaceutics

SN - 0939-6411

IS - 1

ER -