Inter- og intraindividuelle variationer i metformins farmakokinetik - betydning af gener og lægemiddelinteraktioner
we will examine the effect of gene variants in the Organic Cation Transporter 1 (encoded by the SLC22A1 gene also known as OCT1) on the systemic exposure of morphine in a cohort of patients undergoing planned colon or rectum surgery receiving intravenous (iv) morphine during and after the operation. We will also study the impact of OCT1 pharmacogenetics on the total selfadministered dose of morphine, time to first self-administered dose as well as the analgesic response and adverse drug effects.
Morphine exists in it´s protonated, i.e. cationic, form at physiologic pH, and is therefore transported across cell membranes by cation transporters. The OCT1 transporter is located on the sinusoidal membrane of hepatocytes, and it transports morphine into the hepatocytes where it is glucuronidated to the active metabolites morphine-6-glucuronide (M6G) and inactive metabolite M3G.
The study is based on the hypothesis that morphine given intravenously is metabolized more slowly in patients with one or two loss-of-function alleles (v) in the OCT1 due to slow transport into the liver compared with patients with two wild-type (wt) alleles. We also hypothesize that patients with the v/v or v/wt genotypes require lower self-administered doses of morphine and experience a longer time before the first self-administered dose of morphine is needed in order to avoid pain, but do not suffer from less adverse effects than wt/wt patients.
Data and biological material
Data: concentrations of morphine and its metabolites; OCT1 status. Pain at rest and during activity, opioid side effects and level of sedation will be registered at regular time intervals. The total use and time interval for morphine dosing will be registered.
Biological material: blood
Collaborating researchers and departments
Clinical Pharmacology and Pharmaceutics, University of Southern Denmark
- Professor Kim Brøsen, MD, DMSc
- Postdoc Tore Stage, MSc, PhD
Department of Clinical Biochemistry and Pharmacology, Odense University Hospital
- Professor Per Damkier, MD, PhD
- Mette Marie Christensen, MD, PhD
- Troels Bergman, MD, PhD
Department of Anaesthesiology, Odense University hospital
- Stine Thorhauge Zwisler, MD, PhD
Department of Anaesthesiology, South-West Jutland Hospital.
- Rasmus Hjelmar Petersen, MD
- Morten Overgaard, MD
Publications associated with the project
Kuhlmann I, Arnspang Pedersen S, Skov Esbech P, Bjerregaard Stage T, Hougaard Christensen MM, Brøsen K. Using a limited sampling strategy to investigate the interindividual pharmacokinetic variability in metformin: A large prospective trial. Br J Clin Pharmacol. 2021 Apr;87(4):1963-1969. doi: 10.1111/bcp.14591. Epub 2020 Nov 13. PMID: 33118168.
Kuhlmann I, Hjelmar Petersen R, Overgaard M, Dornonville de la Cour K, Zwisler S, Bjerregaard Stage T, Hougaard Christensen MM, Bergmann TK, Damkier P, Gadegaard Jensen A, Nielsen F, Brøsen K. No significant influence of OCT1 genotypes on the pharmacokinetics of morphine in adult surgical patients. Basic Clin Pharmacol Toxicol. 2022 Jan;130(1):93-102. doi: 10.1111/bcpt.13667. Epub 2021 Oct 26. PMID: 34599645.
Kuhlmann I, Nøddebo Nyrup A, Bjerregaard Stage T, Hougaard Christensen MM, Korshøj Bergmann T, Damkier P, Nielsen F, Højlund K, Brøsen K. Oral and intravenous pharmacokinetics of metformin with and without oral codeine intake in healthy subjects: A cross-over study. Clin Transl Sci. 2021 Nov;14(6):2408-2419. doi: 10.1111/cts.13107. Epub 2021 Aug 12. PMID: 34268884; PMCID: PMC8604249.