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 journalArticlepeer-review

33 Scopus citations

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 (US)
Pages (from-to)313-325
Number of pages13
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Volume70
Issue number1
DOIs
StatePublished - 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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