title: The concentration-effect relationship of quinine-induced hearing impairment.
abstract: Quinine-induced reversible hearing impairment at the frequencies of 1000 and 2000 Hz was investigated in healthy volunteers to analyze the plasma concentration-effect relationship of the drug. Six subjects were given two identical oral doses of quinine and a constant rate infusion of quinine over 6 hours (15 mg.kg-1) on three separate occasions. A simple pharmacodynamic model, E = k.C gamma (in which E is effect, k is a proportionality constant, C is drug concentration, and the exponent gamma is a fitting parameter), was found to describe well the relationship between hearing impairment and quinine concentrations in a hypothetical effect compartment. No statistical differences were found in the estimated parameters when the three dosings were compared, indicating that quinine-induced hearing impairment is independent of route of administration. The first-order rate constant (keo), linking plasma concentrations to the concentrations in the effect compartment, was (mean +/- SD) 0.71 +/- 0.19 and 0.99 +/- 0.37 hr-1 for 1000 and 2000 Hz, respectively. The corresponding values of k were 0.15 +/- 0.10 and 0.12 +/- 0.19 and the values of gamma were 2.13 +/- 0.57 and 3.44 +/- 1.04 for 1000 and 2000 Hz, respectively. Effect was also analyzed by semiparametric pharmacodynamic modeling, which gave results comparable to those obtained with the link model. We conclude that a simple power function is a reliable pharmacodynamic model for describing quinine-induced hearing impairment in healthy subjects.
authors.affiliation: Department of Clinical Pharmacology, Huddinge University Hospital, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Paintaud
authors.forename: G
authors.initials: G
authors.lastname: Alván
authors.forename: E
authors.initials: E
authors.lastname: Berninger
authors.forename: L L
authors.initials: LL
authors.lastname: Gustafsson
authors.forename: E
authors.initials: E
authors.lastname: Idrizbegovic
authors.forename: K K
authors.initials: KK
authors.lastname: Karlsson
authors.forename: M
authors.initials: M
authors.lastname: Wakelkamp
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D004305:Dose-Response Relationship, Drug; D005260:Female; D034381:Hearing Loss / Q000139:chemically induced*; D006801:Humans; D007262:Infusions, Intravenous; D016014:Linear Models; D008297:Male; D011803:Quinine / Q000008:administration & dosage* / Q000633:toxicity*; D015203:Reproducibility of Results
chemical_list: D011803:Quinine