Effect of non-instantaneous disposition on the general measures of distribution kinetics in a modified mammillary compartmental model

A theoretical investigation on the evaluation of the general measures of distribution kinetics is proposed by taking into account the non-instantaneous drug disposition in the central compartment after a bolus intravenous injection. The analytical expressions for the drug concentration, the area under curve (AUC), the mean equilibrium time (MEQT), and the clearance (CL) are derived. Comparing the present model with the corresponding instantaneous distribution model (IDM), we found that the latter underestimates the AUC value and overestimates the MEQT and CL values. The following situations lead to a greater discrepancy in the AUC and MEQT values between the present model and the IDM in general: (1) a greater number of compartments; (2) a slower blood-circulation flow rate; (3) a smaller steady-state volume of distribution, and (4) a larger intercompartmental clearance. For a large steady-state volume of distribution, the deviation in the MEQT value from the present model due to the assumption of instantaneous distribution for a large intercompartmental clearance is more serious than that for a small intercompartmental clearance. For a small steady-state volume of distribution, the reverse is true. The present model can describe the distribution of anesthetics such as isoflurane, enflurane, halothane and methoxyflurane in humans. An increase in mass-transfer rate constant from central compartment (CC) to peripheral compartment (PC) has the effect of a decrease in AUC of CC, and the reverse is true for mass-transfer rate constant from PC to CC. Drug concentration in PC (Ci) increases with time and at a fixed time, C-1>C-2>C-3>C-4. AUC of PC decreases as volume of PC increases.