A quantitative alternative to the hysteresis plot for measurement of drug transit time

Hysteresis plots can be used to examine pharmacokinetic data in which there is a transport delay between drug concentrations at two sites in the body (e.g., in blood entering and leaving an organ). However, the area enclosed by the hysteresis "loop" does not provide quantitative information about the magnitude of the delay.

A quick, graphical, and model independent alternative to the hysteresis plot (an "area fraction plot") was developed for a spreadsheet program on a personal computer. It has the advantage that the area enclosed by the "loop" is the mean transit time (MTT) of the transport delay. The method was based on plotting the cumulative area under the concentration-time curve as a fraction of the total area under curve for each site, and is a type of moment analysis. The method is described and was validated by application to simulated data sets. It was also applied to previously published data to calculate the MTT of lidocaine in the lungs and hindquarters of conscious, instrumented sheep.

The validation process showed the area fraction plot was relatively insensitive to integration errors even with moderately noisy data sets. However, failing to analyse the data up to the time point where pseudo-equilibrium was re-established could result in potentially large underestimates of the transit time. The MTT of lidocaine (mean+/-S.E.M.) in the lungs of five sheep was rapid (0.61+/-0.15 min), and 14.2+/-3.1% of the lidocaine was retained in the lungs. The values were in good agreement with values obtained via structural modelling of the same data. The MTT of lidocaine in the hindquarters was 10.6+/-0.9 min, and the retention was 25.2+/-3.1%.

The method can be used in the same situations as a hysteresis plot, but provides additional quantitative information about the transport delay causing the hysteresis.