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Pharmacokinetic and pharmacodynamic analysis of antidiuretic peptides

Callréus, Torbjörn LU (1999)
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... (More)
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. (Less)
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author
opponent
  • Professor Dahlqvist, Rune, University Hospital, S-90185 Umeå
organization
publishing date
type
Thesis
publication status
published
subject
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
pages
120 pages
publisher
Department of Clinical Pharmacology, Lund University Hospital
defense location
F-sal 4, Lund University Hospital
defense date
1999-05-21 10:15
external identifiers
  • Other:ISRN: LUMEDW/MECF-1043-SE
ISBN
91-628-3568-8
language
English
LU publication?
yes
id
7d24fb3e-e153-4d46-a25d-ba325de6698f (old id 39532)
date added to LUP
2007-06-20 13:06:32
date last changed
2016-09-19 08:45:04
@misc{7d24fb3e-e153-4d46-a25d-ba325de6698f,
  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.},
  author       = {Callréus, Torbjörn},
  isbn         = {91-628-3568-8},
  keyword      = {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},
  language     = {eng},
  pages        = {120},
  publisher    = {ARRAY(0x950de98)},
  title        = {Pharmacokinetic and pharmacodynamic analysis of antidiuretic peptides},
  year         = {1999},
}