title: Metabolic acidosis with topiramate and zonisamide: an assessment of its severity and predictors.
abstract: OBJECTIVE
  Carbonic anhydrase (CA) inhibitors topiramate and zonisamide can induce metabolic acidosis in some patients. Our aims were to assess the prevalence and severity of this acidosis and to determine its predictors.
  
  
  METHODS
  For 70 patients established on treatment with topiramate (n=55) or zonisamide (n=14) or both (n=1), we measured electrolytes, and genotyped single nucleotide polymorphisms (SNPs) in the main renal CA isoenzymes (II, IV and XII).
  
  
  RESULTS
  Twenty-six percent of patients had a metabolic acidosis (serum bicarbonate <20 mmol/l). The mean serum bicarbonate of patients taking topiramate was significantly lower than those taking zonisamide (P=0.002). We found no association between serum bicarbonate and the dose of drug or the duration of treatment. Serum bicarbonate levels were associated with the CA type XII SNPs rs2306719 (P=0.006 by one-way analysis of variance) and rs4984241 (P=0.015), but this association was not strong enough to survive correction for multiple testing.
  
  
  CONCLUSIONS
  The development of acidosis with topiramate and zonisamide is not determined by drug dose or by treatment duration, but may be influenced by polymorphisms in the gene for CA type XII. The aforementioned SNPs lie 9.8 kb apart in intron 1 of the CA type XII gene, and deserve further study in a larger cohort of patients.
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. nasir.mirza@liv.ac.uk
authors.forename: Nasir S
authors.initials: NS
authors.lastname: Mirza
authors.forename: Ana
authors.initials: A
authors.lastname: Alfirevic
authors.forename: Andrea
authors.initials: A
authors.lastname: Jorgensen
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Marson
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
mesh_terms: D000136:Acid-Base Equilibrium / Q000187:drug effects; D000141:Acidosis, Renal Tubular / Q000139:chemically induced / Q000453:epidemiology* / Q000235:genetics*; D000328:Adult; D000368:Aged; D002257:Carbonic Anhydrase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D002256:Carbonic Anhydrases / Q000235:genetics*; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D005632:Fructose / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D055106:Genome-Wide Association Study; D006801:Humans; D007555:Isoxazoles / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D012720:Severity of Illness Index; D000077236:Topiramate; D055815:Young Adult; D000078305:Zonisamide
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D007555:Isoxazoles; D000077236:Topiramate; D005632:Fructose; D000078305:Zonisamide; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII