Pharmacokinetic and pharmacodynamic analysis of antidiuretic peptides

Research output: ThesisDoctoral Thesis (compilation)

Abstract

The clinical pharmacology of desmopressin and a new vasopressin analogue (F992) was investigated in healthy human subjects. The common procedure of overhydration of healthy volunteers when studying the antidiuretic effect of a drug, may affect the pharmacokinetics, in particular the volumes of distribution. Hence, the estimated parameters may not be relevant to euhydrated patients. F992 was found safe to administer as infusion to overhydrated male volunteers. The results suggest that F992 has a longer half-life and a lower potency than the widely used peptide desmopressin. The influence of changes in gastrointestinal motility, induced by erythromycin and loperamide, on the pharmacokinetics of orally administered desmopressin was investigated. Presumably due to a slowing of gastrointestinal motility, pretreatment with loperamide significantly increases the gastrointestinal absorption of desmopressin. Except for a shortening of tmax, pretreatment with erythromycin did not significantly influence the absorption of the drug. In one study, the pharmacokinetics and pharmacodynamics of desmopressin were investigated in healthy male subjects at different levels of hydration. In this particular study, we did not find any significant effects of different levels of hydration on the estimates of the pharmacokinetic and pharmacodynamic model parameters. The indirect-response model used in the study to estimate the pharmacodynamic parameters, offers a mechanistic approach of modelling the effect of desmopressin in overhydrated subjects. The influence of lithium, on the antidiuretic effect of desmopressin in overhydrated subjects, was investigated with the previously used indirect-response model. The results demonstrate how the IC50 value increases as a result of higher lithium concentrations and urine flow at baseline, whereas higher urine osmolarity at baseline decreases the IC50 value. We found that an indirect-response model can be a useful tool in investigating and describing the interaction between drugs, in this particular case, between lithium and desmopressin.

Details

Authors
  • Torbjörn Callréus
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medicinal Chemistry
  • Pharmacology and Toxicology

Keywords

  • lithium, indirect-response model, pharmacodynamics, pharmacokinetics, gastrointestinal absorption, gastrointestinal motility, loperamide, erythromycin, antidiuretic effect, desmopressin, overhydration, vasopressin analogue (F992), interaction, Pharmacological sciences, pharmacognosy, pharmacy, toxicology, Farmakologi, farmakognosi, farmaci, toxikologi
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
  • [unknown], [unknown], Supervisor, External person
Award date1999 May 21
Publisher
  • Department of Clinical Pharmacology, Lund University Hospital
Print ISBNs91-628-3568-8
Publication statusPublished - 1999
Publication categoryResearch

Bibliographic note

Defence details Date: 1999-05-21 Time: 10:15 Place: F-sal 4, Lund University Hospital External reviewer(s) Name: Dahlqvist, Rune Title: Professor Affiliation: University Hospital, S-90185 Umeå ---