We wish to comment on the paper by Mahmood, `Prediction of absolute bioavailability for drugs using oral and renal clearance following a single oral dose: a critical review'. 1 We ®rst present below a summary of the main features of the novel method, its validation, and the prerequisites for its successful application before providing comments on the above-mentioned paper.
The novel method to calculate absolute bioavailability from oral data was recently proposed by Hinderling and Shi 2 and others. 3 The novel method's main application is with data sets obtained simultaneously in renal failure patients and control subjects for drugs for which the intended mode of administration is oral and intravenous data are not available or cannot be gathered. As stated earlier, 2 optimal conditions for application of the novel method, which computes mean absolute bioavailability from the reciprocal of the slope of a plot of oral total clearance, Cl po , against renal clearance, Cl r , are met if the clearance data are from (i) drugs for which renal clearance in healthy subjects represents a major fraction of the total (intravenous) clearance, Cl iv , and (ii) subjects with widely varying renal function (creatinine clearance). Additional conditions that must be met for a successful application of the novel method are that the drug must exhibit ®rst-order disposition (distribution, elimination) kinetics and that absolute bioavailability and nonrenal clearance must be independent of renal function.
This method was validated by comparing the absolute bioavailability estimates obtained by the novel and classical methods for sematilide HCl, a class III antiarrhythmic drug, which is predominately excreted unchanged by the kidney. 2 Data were available from a single randomized crossover study with intravenous and oral treatments of sematilide HCl in subjects with widely varying renal functions (creatinine clearance =14±183 mL min 71 ), allowing computation of estimates by both methods using the same database. The values for absolute bioavailability by the classical method were estimated from the ratio of the respective dose corrected areas under the drug concentration time curves. The respective mean estimates for absolute bioavailability for