title: Marked interindividual variability in the response to selective inhibitors of cyclooxygenase-2.
abstract: OBJECTIVE
  Variability in response to drugs may influence both efficacy and safety. Cyclooxygenase (COX)-2 inhibitors pose a cardiovascular risk by potentially increasing the likelihood of thrombosis, hypertension, and atherogenesis. Differences between individuals in the response to COX-2 inhibitors would be expected to influence their susceptibility to cardiovascular complications. We examined the variability in degree and selectivity of COX-2 inhibition in humans in response to celecoxib and rofecoxib.
  
  
  METHODS
  Fifty healthy volunteers received placebo, rofecoxib (25 mg), and celecoxib (200 mg), randomized by order. COX-1 and COX-2 inhibition was determined using ex vivo and in vivo indices of enzymatic activity. A subset of 5 individuals underwent 5 replicate studies to estimate variability in drug response both within and between subjects.
  
  
  RESULTS
  Despite the higher COX-2 selectivity of rofecoxib in vitro, the average selectivity attained by 25 mg rofecoxib and 200 mg celecoxib in vivo were not different. However, there was considerable variability at an individual level in the degree of COX-2 inhibition and selectivity attained by both drugs. Approximately one third of the variability was attributable to differences between individuals, suggesting the contribution of genetic sources of variance, such as candidate polymorphisms detected in COX-1 and CYP2C9.
  
  
  CONCLUSIONS
  The actual degree of selectivity for inhibition of COX-2 achieved by the coxibs relates both to chemical properties of the drug and to factors within an individual that modulate drug response. These sources of variability might be exploited to identify patients uniquely susceptible to benefit or at developing risk of cardiovascular complications.
authors.affiliation: The Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6084, USA.
authors.forename: Susanne
authors.initials: S
authors.lastname: Fries
authors.forename: Tilo
authors.initials: T
authors.lastname: Grosser
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Price
authors.forename: John A
authors.initials: JA
authors.lastname: Lawson
authors.forename: Shiv
authors.initials: S
authors.lastname: Kapoor
authors.forename: Susan
authors.initials: S
authors.lastname: DeMarco
authors.forename: Mathew T
authors.initials: MT
authors.lastname: Pletcher
authors.forename: Tim
authors.initials: T
authors.lastname: Wiltshire
authors.forename: Garret A
authors.initials: GA
authors.lastname: FitzGerald
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000139:chemically induced; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D065729:Cytochrome P-450 CYP2C9; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D007783:Lactones / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D010919:Placebos; D011110:Polymorphism, Genetic; D015203:Reproducibility of Results; D018570:Risk Assessment; D013450:Sulfones / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D013927:Thrombosis / Q000139:chemically induced
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D010919:Placebos; D013450:Sulfones; C116926:rofecoxib; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D051546:Cyclooxygenase 2