This study will address the following question: Does imatinib influence the pharmacokinetics of metformin in healthy volunteers? Recent studies in the Giacomini laboratory have indicated that imatinib may block metformin elimination from the kidney by inhibiting organic cation transporter efflux of metformin. 1. The investigators hypothesize that the addition of imatinib to metformin therapy will reduce the renal clearance (CLR) of metformin leading to increased plasma concentrations and risk for toxicities 2. Knowledge of the pharmacokinetic interaction profile of metformin with organic cation transporter inhibitors, such as imatinib, is important to help develop safer more effective drug therapy with reduced side effects.

Screening Procedures:

Prior to enrollment, subjects will be asked to come to the Clinical and Translational Science (CTSI) Clinical Research Centre (CRC) at San Francisco General Hospital (SFGH). The study protocol and procedures will be explained in detail, all questions will be answered, and subjects will be provided a consent form to sign. The screening visit must be conducted within 14 days of the first inpatient visit i.e. first metformin alone or metformin and imatinib dosing day.

Only after subjects have consented to participate in the study will the screening procedures commence. All subjects recruited in this study will have already consented to the pharmacogenomics in ethnically diverse populations (SOPHIE) study, a previously established cohort of healthy people living in San Francisco. A review of the subject's medical history and health questionnaire will be conducted, by the research staff, to re-assess health status and confirm eligibility. Changes in medical or drug use history will be noted during the study.

During the screening visit, vital signs as well as blood and urine samples will be taken from all subjects for laboratory analysis. A single blood sample (10 mL) will be taken by venipuncture to measure a complete blood count (CBC), electrolytes, blood urea nitrogen (BUN), creatinine, and liver function tests (LFTs) to screen for anemia and renal or hepatic insufficiency (see Inclusion/Exclusion Criteria).

After their screening visit, an equal number of subjects will be randomized, by a random number generator in excel, into one of the two study arms; metformin alone followed by the co-administration of metformin and imatinib.

Procedures During Main Study:

Randomized Study Visit Arm 1: Metformin alone Subjects will report to the CRC at approximately 7:30 AM, after an overnight fast of at least 10 hours (since approximately 10:00 PM). Vital signs and a brief history will be taken upon arrival. If all inclusion/exclusion criteria are met, one intravenous (IV) catheter will be inserted into a forearm vein to facilitate blood sampling. An initial blood sample of 10 mL will be drawn from the IV line for the determination of plasma metformin, creatinine, and imatinib concentrations prior to the administration of metformin (i.e. baseline measurement). Next each subject will receive an oral dose of 1000 mg of metformin with 8 oz of water followed by an oral dose of 850mg. Blood samples (5 mL each) will then be drawn at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, and 24 hours post-dose for the determination of plasma metformin and imatinib concentrations. An additional 5 mL of blood will be drawn at the 6-hour and 12-hour time points for the measurement of serum creatinine to allow the calculation of creatinine clearance (CLcr). Blood samples obtained by finger prick will be taken at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5 and 4 hours after ingestion of metformin (total of 0.1 mL) to measure blood glucose levels. Additional biomarkers of metformin/imatinib response and toxicities, such as plasma insulin, glucose and AMPK activation, may also be determined on the blood samples collected. Subjects will remain at the CRC and receive standardized meals starting 4 hours post metformin dosing. Subjects will be discharged and allowed to go home the following morning after the collection for the 24 hour blood and urine sample at approximately 8 AM. All blood samples will be centrifuged, and the plasma separated immediately and stored at -80oC until analysis.

Urine collection:Subjects will be asked to void their bladder prior to metformin administration (baseline urine sample) and to drink 8 oz of water every 4 hours to maintain urine flow and pH. Aliquots of urine will be collected for the following time frames: 0-2, 2-4, 4-8, 8-12, and 12-24 hours post metformin dosing. Additionally, aliquots from collections taken between 0-12 and 0-24 hours will be pooled for analysis of creatinine. Subjects will be advised to collect all urine produced during the inpatient visit. The volume and pH of each urine collection will be recorded and an aliquot (20 mL) from each collection period will be stored at -80°C for determination of urinary metformin and creatinine concentrations.

Randomized Study Visit Day 2:Co-administration of metformin with imatinib Subjects will present to the CRC after an overnight fast as previously described. After the collection of the baseline blood and urine samples, subjects will receive an oral dose of 600 mg imatinib and 1000 mg of metformin with 8 oz of water followed by an oral dose of 850mg. The study procedures described in "Randomized Study Visit Day 1" and "Urine collection" will be repeated.

Study Restrictions:

Concomitant Medications:

The study requires that healthy participants refrain from taking any medications (except for daily vitamins or oral contraceptives) for the duration of the study, in particular medication(s) that interfere with the pharmacokinetics of metformin or imatinib (See Exclusion criteria 13.7).

Other Study Restrictions:

Subjects will be required to use adequate contraceptive means to avoid pregnancy throughout the study. Subjects must remain within the CRC throughout the two 24 hour inpatient visits unless accompanied by a CRC staff member. Subjects are to refrain from smoking and from ingesting caffeine, alcohol, orange and grapefruit juice containing products from the night before each inpatient study day until the study is complete, approximately 24 hours after dosing.

Clinical and Laboratory Determinations:

Measurement of metformin, creatinine, imatinib and CGP74588 in plasma and urine will be preformed by High Performance Liquid Chromatography (HPLC) with tandem mass spectrometry (MS/MS) using assays previously described and validated.

Hematology, Blood Chemistry and Urinalysis:

The following standard biochemistry, blood chemistry and urinalysis will be performed at the screening visit:

1. Hematology, (Complete Blood Count with differential, CDP): WBC with differential, red blood cells (RBC), RBC indices (HGB, HCT, MCV, MCH, MCHC) and platelet count.
2. Blood chemistry (Metabolic Comprehensive Panel, METC): sodium, potassium, chloride, carbon dioxide, creatinine, blood urea nitrogen, glucose, calcium, bilirubin (total), phosphate (total), AST, ALT, albumin and alkaline phosphatase
3. Urinalysis: urine protein (dipstick) and blood (dipstick).

Inclusion Criteria:

• Age 18-45 years
• Male or female
• If female, using appropriate contraception
• Healthy as judged by medical examination, medical history and normal biochemical and hematological measures
• Normal urinalysis and renal function
• Understand the nature and purpose of the study and provide informed consent

Exclusion Criteria:

• Pregnant or lactating woman (female subjects will have a urine pregnancy test at the screening visit)
• Abnormal bone marrow function (leukocyte, neutrophil, or platelet counts outside the normal range)
• History of hypersensitivity or allergic reaction to metformin or imatinib
• Risk of congestive heart failure requiring pharmacologic treatment (medical history)
• History of renal or hepatic dysfunction (e.g., CLcr <60mL/min, ALT >80U/L, AST>60 U/L) Anemic (hemoglobin <12 g/dL)
• Use of any medications (including over the counter products, herbal products, or mineral supplements) with the exception of a daily vitamin or oral contraceptives. In particular use of medications that are known to interfere with the pharmacokinetics of metformin and imatinib such as cimetidine, cetirizine, ketoconazole, procainamide, St. John's Wort, and testosterone are prohibited.
• Subjects are undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function
• Laboratory parameters that are more than 2 standard deviations from the laboratory mean
• Subject carries a MATE1 gene variant that is predicted to effect MATE1 protein expression