Application of the Loo-Riegelman absorption method.

The Loo-Reigelman absorption method provides the correct A infinity/V1 value and the correct rate constant ka (if absorption is first order), whether metabolism occurs in compartment 1 only, compartment 2 only, or both compartments 1 and 2 of the two-compartment open models. In cases where there is metabolism in compartment 2, the disposition parameters estimated from intravenous data are only apparent and not the real values. The correct A infinity/V1 and ka values are obtained, however, only under conditions not hithertofore specified. Thes conditions are that there must be essentially no bias in the disposition parameters k12, k21 and kel, and in the C0 value estimated from the intravenous data, and that in the oral study a large number of interpolated plasma concentrations, as well as the observed plasma concentrations, must be used, especially for drugs with long half-lives. It is shown that application of the Guggenheim method to the initial At/V1, t values frequently provides a better method of estimating A infinity/V1 and ka than the classical method. If biased disposition parameters are used in application of the Loo-Reigelman method oral data, then essentially the correct ovalue of ka will be estimated, but the estimate of A infinity/V1 will be approximately equal to the true value of A infinity/V1 multiplied by the ratio of the biased C0 value (obtained in fitting the intravenous data) to the true C0 value of the intravenous data. The above indicates that intravenous data should be fitted by computer until there are no systematic deviations or trends and as small a sum of squared deviations as possible is obtainedmthe oral data should be fitted by spline or Akima methods, or similar procedures, to produce a function which passes through each observed plasma concentration and at the same time provides a large number of interpolated concentration data.