Inter- and Intra-individual Variations in Metformin Pharmacokinetics - The Importance of Genes and Drug Interactions
Condition: Metformin; Organic Cation Transporter 1; Codeine
Study type: Interventional
Phase: Phase 1

Summary: 
      The investigators aim to investigate the interindividual variation in metformin AUC in a
      large cohort of healthy volunteers after a single dose of metformin. Part 1 is driven by the
      hypothesis that metformin AUC and renal clearance exhibit significant interindividual
      variation. However this has never been documented in a large cohort of healthy volunteers.

      The investigators aim to investigate the potential interaction between codeine and metformin
      in the intestine. The hypothesis underlying part 3 is that the increased risk of early
      discontinuation of metformin during co-administration with codeine is primarily due to local
      inhibition of OCT1 via codeine at the intestinal level.
    

Detailed description: 
      Part 1: The investigators intend to investigate the inter-individual variation in metformin
      Area Under Plasma Concentration Curve (AUC) following a single dose of oral metformin based
      on the plasma concentration of metformin after 3 and 10 hours and urine collection for 24
      hours . Part 2: The investigators intend to contribute with DNA and metformin AUC
      determinations from subjects from part 1 to a major international study that aime to
      highlight the Genome Wide Association (GWA) between the entire genome and variations in
      metformin pharmacokinetics (AUC) in a large group of healthy subjects and patients. Part 3:
      The investigators aim to investigate the potential interaction between codeine and metformin
      in the intestine.

      The investigators secondary objective in part 3 is to investigate if the plasma concentration
      of morphine increases when codeine and metformin are given together due to competitive
      inhibition of the Organic cation transporter 1 (OCT1) transport protein (in the liver).
      Furthermore, the investigators will measure lactate after metformin ingestion as a proxy for
      metformin's effect on the intestinal mucosa, both after oral and intravenous metformin
    

Intervention name(s): Oral metformin; Intravenous metformin; Oral codeine and oral metformin; Oral codeine and intravenous metformin
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): The study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous metformin; The study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous metformin; The study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous metformin; The study was designed as a randomized, cross-over trial with a washout period of at least 1 week between the phases. Metformin was given both orally and through an intravenous route to be able to determine the absolute bioavailability of metformin. Metformin was given alone and together with codeine to investigate a potential interaction between the drugs. Lactate was measured as a proxy for metformin effect on the intestinal mucosa, both after oral and intravenous metformin
Intervention MeSH terms: Metformin; Codeine
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: In part 1 a single group of healthy volunteers will ingest a single dosis of metformin and then have a blood sample drawn after 3 and 10 hours.
In part 3, 18 healthy subjects will be randomized to ingest: a) oral metformin b) intravenous metformin c) 4 pills of codeine with the 5th taken together with oral metformin and d) 4 pills of codeine with the 5th taken together with intravenous metformin.
Masking: None (Open Label)
Primary purpose: Basic Science