Hearing impairment related to plasma quinine concentration in healthy volunteers

1. Hearing impairment was investigated in six healthy volunteers who received oral doses of 5, 10 and 15 mg kg-1 quinine single-blind and in random order. 2. The plasma concentration of quinine was followed for 48 h and the time course was fitted by a linear one compartment pharmacokinetic model. 3. Hearing thresholds were measured by pure tone audiometry. There was a delay between impairment in hearing and change in plasma quinine concentration. Thus the method of effect compartment modelling was applied. 4. The effect on hearing (L), measured as a shift in hearing threshold (dB), was used to estimate the rate constant for elimination of drug from the assumed effect compartment (ke0) and two parameters specifying the effect model (gamma and k). The effect model applied was L = 10 (log k + gamma x log Ce) where Ce is the calculated drug concentration in the effect compartment. This model is a logarithmic transform of a power expression equivalent to the Hill equation at the lower end of the effect range. In all experiments where there was a clear effect on hearing, convergence on a set of parameter estimates occurred, but inter- and intraindividual variability was large. The mean value of ke0 was 3.32 +/- 5.93 h-1 s.d., for gamma it was 1.73 +/- 1.14 s.d. and for k it was 0.59 +/- 0.66 s.d.