title: The Effect of Famotidine, a MATE1-Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin.
abstract: Pharmacokinetic outcomes of transporter-mediated drug-drug interactions (TMDDIs) are increasingly being evaluated clinically. The goal of our study was to determine the effects of selective inhibition of multidrug and toxin extrusion protein 1 (MATE1), using famotidine, on the pharmacokinetics and pharmacodynamics of metformin in healthy volunteers.
  
  
  
  Volunteers received metformin alone or with famotidine in a crossover design. As a positive control, the longitudinal effects of famotidine on the plasma levels of creatinine (an endogenous substrate of MATE1) were quantified in parallel. Famotidine unbound concentrations in plasma reached 1 µM, thus exceeding the in vitro concentrations that inhibit MATE1 [concentration of drug producing 50 % inhibition (IC50) 0.25 µM]. Based on current regulatory guidance, these concentrations are expected to inhibit MATE1 clinically [i.e. maximum unbound plasma drug concentration (C max,u)/IC50 >0.1].
  
  
  
  Consistent with MATE1 inhibition, famotidine administration significantly altered creatinine plasma and urine levels in opposing directions (p < 0.005). Interestingly, famotidine increased the estimated bioavailability of metformin [cumulative amount of unchanged drug excreted in urine from time zero to infinity (A e∞)/dose; p < 0.005] without affecting its systemic exposure [area under the plasma concentration-time curve (AUC) or maximum concentration in plasma (C max)] as a result of a counteracting increase in metformin renal clearance. Moreover, metformin-famotidine co-therapy caused a transient effect on oral glucose tolerance tests [area under the glucose plasma concentration-time curve between time zero and 0.5 h (AUCglu,0.5); p < 0.005].
  
  
  
  These results suggest that famotidine may improve the bioavailability and enhance the renal clearance of metformin.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 1550 4th St, RH 584, Box 2911, San Francisco, CA, 94158, USA.|Department of Clinical Pharmacy, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Hibma
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 1550 4th St, RH 584, Box 2911, San Francisco, CA, 94158, USA.
authors.forename: Arik A
authors.initials: AA
authors.lastname: Zur
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 1550 4th St, RH 584, Box 2911, San Francisco, CA, 94158, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Castro
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 1550 4th St, RH 584, Box 2911, San Francisco, CA, 94158, USA.
authors.forename: Matthias B
authors.initials: MB
authors.lastname: Wittwer
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 1550 4th St, RH 584, Box 2911, San Francisco, CA, 94158, USA.
authors.forename: Ron J
authors.initials: RJ
authors.lastname: Keizer
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 1550 4th St, RH 584, Box 2911, San Francisco, CA, 94158, USA.
authors.forename: Sook Wah
authors.initials: SW
authors.lastname: Yee
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 1550 4th St, RH 584, Box 2911, San Francisco, CA, 94158, USA.
authors.forename: Srijib
authors.initials: S
authors.lastname: Goswami
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 1550 4th St, RH 584, Box 2911, San Francisco, CA, 94158, USA.
authors.forename: Sophie L
authors.initials: SL
authors.lastname: Stocker
authors.affiliation: Optivia Biotechnology Inc., Menlo Park, CA, USA.
authors.forename: Xuexiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Optivia Biotechnology Inc., Menlo Park, CA, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Brett
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 1550 4th St, RH 584, Box 2911, San Francisco, CA, 94158, USA.
authors.forename: Radojka M
authors.initials: RM
authors.lastname: Savic
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 1550 4th St, RH 584, Box 2911, San Francisco, CA, 94158, USA. kathy.giacomini@ucsf.edu.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Giacomini
mesh_terms: D000328:Adult; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001786:Blood Glucose; D003404:Creatinine / Q000097:blood / Q000652:urine; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D015738:Famotidine / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics*; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D000897:Anti-Ulcer Agents; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; C521869:SLC47A1 protein, human; D015738:Famotidine; D008687:Metformin; D003404:Creatinine