Studies on intrinsic and extrinsic sources of variability in pharmacokinetics and pharmacodynamics

Johanna Mercke Odeberg

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Variability in pharmacokinetic and pharmacodynamic parameters between individuals can be due to intrinsic and extrinsic factors. In this thesis three different areas regarding sources of variability have been investigated. 1. Formulation properties as an extrinsic source of variability. Lipophilic substances often have poor oral bioavailability and high inter- and intraindividual variability. High fat meals can increase the bioavailability. Two lipophilic substances, astaxanthin and cyclosporine, were incorporated in different lipid based formulations, given orally to healthy volunteers, and shown to alter the bioavailability when compared to reference substances. The combination of different lipid excipients, their ratios and the degree of drug incorporation were factors shown to affect the drug bioavailability. The use of a rational formulation approach in the study with cyclosporine gave successful information in a limited number of trials. 2. Intrinsic and extrinsic sources of variability in the pharmacokinetics and pharmacodynamic of desmopressin. To evaluate factors that can cause variability both the pharmacokinetics and pharmacodynamics have to be investigated. Desmopressin is a synthetic analogue of the antidiuretic hormone vasopressin. We studied in humans if different levels of water hydration had any influence on especially the pharmacokinetics, and found no statistical evidence for that. An indirect response model was described and verified for the concentration-effect relationship. Further, we investigated sex differences and the impact of concomitant medication with piroxicam , and we found a difference in the pharmacodynamics of desmopressin, but not in the pharmacokinetics.

3. Genetic polymorphism as an intrinsic source of variability in drug metabolism and drug transport. We investigated, in a Swedish cohort (248 individuals) and in a human diversity panel (HDP) (DNA from 14 ethnicities), the prevalence of different polymorphisms and haplotypes in the UGT1A- and MDR1-genes, both being associated with variations in pharmacokinetics. Also, to estimate UGT1A genotype-dependent glucuronidation efficiency, we used the endogenous substrate bilirubin as an indicator. We found that several of the genetic variants investigated in the UGT1A-gene and also the SNP (exon 26, C3435T) in the MDR1 gene are common in the cohort. The HDP indicated differences in prevalence of the allelic variants due to ethnicity. Three major haplotypes of the UGT1A-gene constitute 84% of the allelic variants.

Tools for optimisation, prediction and individualisation of drug treatment are important for attaining the aim of explaining and reducing variability in drug response.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Division of Clinical Chemistry and Pharmacology
Supervisors/Advisors
  • Mercke Odeberg, Johanna, Supervisor
Award date2005 Oct 8
Publisher
Print ISBNs91-85439-83-5
Publication statusPublished - 2005

Bibliographical note

Defence details

Date: 2005-10-08
Time: 09:00
Place: Föreläsningssal 1, Centralblocket, Universitetssjukhuset Lund

External reviewer(s)

Name: Peterson, Curt
Title: Professor
Affiliation: Klinisk farmakologi, Linköpings universitet

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<div class="article_info">Johanna Mercke Odeberg, Å. Lignell, A. Pettersson and P. Höglund. <span class="article_issue_date">2003</span>. <span class="article_title">Oral bioavailability of the antioxidant astaxanthin in humans is enhanced by incorporation of lipid based formulations.</span> <span class="journal_series_title">European Journal of Pharmaceutical Sciences</span>, <span class="journal_volume">vol 19</span> <span class="journal_pages">pp 299-304</span>. <span class="journal_distributor">Elsevier B.V.</span></div>
<div class="article_info">Johanna Mercke Odeberg, P. Kaufmann, K. G. Kroon and P. Höglund. <span class="article_issue_date">2003</span>. <span class="article_title">Lipid drug delivery and rational formulation design for lipophilic drugs with low oral bioavailability, applied to cyclosporine.</span> <span class="journal_series_title">European Journal of Pharmaceutical Sciences</span>, <span class="journal_volume">vol 20</span> <span class="journal_pages">pp 375-382</span>. <span class="journal_distributor">Elsevier B.V.</span></div>
<div class="article_info">J. Mercke Odeberg, J. Andrade, K. Holmberg, P. Höglund and U. Malmqvist. <span class="article_issue_date"></span>. <span class="article_title">Prevalence of polymorphisms in the genes for UGT1A (and corresponding haplotypes) and MDR1 in a Swedish cohort and in a human diversity panel, and the relationship between UGT1A polymorphisms and bilirubin plasma levels in males and females.</span> (manuscript)</div>
<div class="article_info">Johanna Mercke Odeberg, T. Callreus, T. Lundin, E. B. Roth and P. Höglund. <span class="article_issue_date">2004</span>. <span class="article_title">A pharmacokinetic and pharmacodynamic study of desmopressin: evaluating sex differences and the effect of pre-treatment with piroxicam, and further validation of an indirect response model.</span> <span class="journal_series_title">Journal of Pharmacy and Pharmacology</span>, <span class="journal_volume">vol 56</span> <span class="journal_pages">pp 389-398</span>. <span class="journal_distributor">The authors</span></div>
<div class="article_info">T. Callreus, Johanna Mercke Odeberg, S. Lundin and P. Höglund. <span class="article_issue_date">1999</span>. <span class="article_title">Indirect-response modeling of desmopressin at different levels of hydration</span> <span class="journal_series_title">Journal Of Pharmacokinetics and Biopharmaceutics</span>, <span class="journal_volume">vol 27</span> <span class="journal_pages">pp 513.529</span>. <span class="journal_distributor">Plenum Publishing company</span></div>

Subject classification (UKÄ)

  • Medicinal Chemistry
  • Pharmacology and Toxicology

Keywords

  • toxikologi
  • pharmacy
  • pharmacognosy
  • Pharmacological sciences
  • Medicin (människa och djur)
  • Medicine (human and vertebrates)
  • genetic polymorphisms(UGT1A-and MDR1 gene)
  • indirect response model
  • desmopressin
  • oral lipid based formulations
  • farmaci
  • Farmakologi
  • toxicology
  • farmakognosi

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