Celiprolol double-peak occurrence and gastric motility: Nonlinear mixed effects modeling of bioavailability data obtained in dogs View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

1995-06

AUTHORS

Elke Lipka, I-Der Lee, Peter Langguth, Hildegard Spahn-Langguth, Ernst Mutschler, Gordon L. Amidon

ABSTRACT

Investigation of the underlying mechanism leading to inter- and intrasubject variations in the plasma concentration-time profiles of drugs (1) can considerably benefit rational drug therapy. The significant effect of gastric emptying on the rate and extent of celiprolol absorption and its role with respect to double-peak formation was demonstrated in the present study. In four dogs racemic celiprolol was dosed perorally in a crossover design during four different phases of the fasted-state gastric cycle and gastric motility was recorded simultaneously using a manometric measurement system. Intravenous doses were also given to obtain disposition and bioavailability parameters. The blood samples were assayed by a stereoselective HPLC method (2). The time to onset of the active phase of the gastric cycle showed an excellent correlation with the time to celiprolol peak concentration. Furthermore, bioavailability was increased when celiprolol was administered during the active phase. Double peaks were observed when the first active phase was relatively short, suggesting that a portion of the drug remained in the stomach until the next active phase. Population pharmacokinetic modeling of the data with a two-compartment open model with two lag times incorporating the motility data confirmed the effect of time to gastric emptying on the variability of the oral pharmacokinetics of celiprolol. The fasted-state motility phases determine the rate and extent of celiprolol absorption and influence the occurrence of double peaks. Peak plasma levels of celiprolol exhibit less variability if lag times, and therefore gastric emptying times, are taken into consideration. More... »

PAGES

267-286

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/bf02354285

DOI

http://dx.doi.org/10.1007/bf02354285

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1037625560

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/8834196


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