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

doi:10.1016/j.ejpb.2008.02.022

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

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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 (k_g) 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 k_g (k_g(max)) were much greater than those reported for emptying of liquids in the fasted state and were comparable to k_g 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 k_a derived using the time-dependent absorption model were closer to the intrinsic absorption rate constant for caffeine.

Original language	English (US)
Pages (from-to)	313-325
Number of pages	13
Journal	European Journal of Pharmaceutics and Biopharmaceutics
Volume	70
Issue number	1
DOIs	https://doi.org/10.1016/j.ejpb.2008.02.022
State	Published - Sep 2008

Bibliographical note

Funding Information:
This work was supported by NASA Grant No. NAGW-4981. The authors thank the Pharmacia & Upjohn Company (now Pfizer) for the generous donation of resources and materials in the manufacture of the pellets and the General Clinical Research center (GCRC), University of Michigan funded by Grant No. M01 RR00042 from the National Center for Research Resources, National Institutes of Health, US PHS.

Keywords

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

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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.",

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

Abstract

Bibliographical note

Keywords

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