Impact of Genetics on Metformin Pharmacokinetics
Condition: Other Conditions That May Be A Focus of Clinical Attention
Study type: Interventional

Summary: 
      Specific Aims: To compare metformin pharmacokinetics in monozygotic and dizygotic twin pairs.
      Comparing renal clearance of metformin in monozygotic and dizygotic twins will allow us to
      better understand the influence of heredity on variation in renal elimination. Furthermore,
      genotyping renal transporter genes in monozygotic and dizygotic twin pairs with significant
      differences in renal clearance of metformin may give us insight into the genes responsible
      for this variability.
    

Detailed description: 
      Twin studies have long been a valuable tool for examining the relative role of environment
      and heredity in health issues such as disease and drug response. For example, twin studies in
      the 1960's and 1970's showed for the first time that variability in the elimination of many
      drugs was largely influenced by heredity. Monozygotic twin pairs showed little variability in
      the elimination of various drugs while dizygotic twin pairs, sharing only about one half of
      their genes, showed much greater variability. It is now known that the some of the
      variability in drug elimination observed in dizygotic twins was due to genetic differences in
      drug metabolizing enzymes, such as the cytochrome P450's. However, genetic variation in other
      genes, such as membrane transporters may also contribute to variability in drug response.

      Membrane transporters play multiple roles in the body; they help to maintain cellular
      homeostasis through import and export mechanisms and also play an important role in drug
      response, affecting both the pharmacokinetics and pharmacodynamics of drugs. Animal studies
      using mice genetically deficient in drug transporters and reports of drug interaction studies
      involving transporter substrates have provided convincing evidence that the level of function
      of several important drug transporters is an important determinant of drug response.

      The current study will examine differences in the renal clearance of metformin in monozygotic
      and dizygotic twin pairs. Metformin is an antidiabetic drug that has no significant hepatic
      metabolism and is actively secreted by the kidneys. Studies in our lab have shown that
      metformin is a substrate of the human organic cation transporter, hOCT2, which appears to be
      a major transporter involved in the renal secretion of cationic drugs. Data in the literature
      indicate that there is substantial variation in the net secretory clearance of metformin in
      normal, healthy volunteers. In five healthy volunteers, the ratio of renal clearance to
      creatinine clearance ranged from 1.5 to 4.2, nearly a 3-fold variation. We hypothesize that
      genetic variation in secretory transporters in the kidney, like hOCT2, may be responsible for
      the inter-individual differences in the secretory clearance of metformin and other drugs.
      Studies examining renal clearance of metformin in monozygotic and dizygotic twins will allow
      us to better understand the influence of heredity on variation in renal elimination.
      Furthermore, genotyping monozygotic and dizygotic twin pairs with significant differences in
      renal clearance of metformin may give us insight into the genes responsible for this
      variability.
    

Intervention name(s): Metformin HCl
Intervention type(s): Drug
Intervention description(s): Subjects will be given a single oral dose in tablet form containing 850 mg of metformin
Other intervention name(s): GLUCOPHAGE
Intervention MeSH terms: Metformin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Healthy Control Twins