Assuming peripheral elimination: Its impact on the estimation of pharmacokinetic parameters of muscle relaxants

For anesthetic drugs undergoing nonorgan-based elimination, there is a defi nite trend towards using pharmacokinetic (PK) models in which elimination c an occur from both central (k(10)) and peripheral compartments (k(20)) AS t he latter cannot be assessed directly assumptions have to be made regarding its value. The primary purpose of this paper is to valuate the impact of a ssuming various degrees of peripheral elimination on the estimation of PK p arameters. For doing so, an explanatory model is presented where previously published data from our laboratory on three muscle relaxants, i.e., atracu rium, doxacurium, and mivacurium, are used for simulations. The mathematica l aspects for this explanatory model as well as for. two specific applicati ons are detailed. Our simulations show that muscle relaxants having a short elimination half-life are more affected by the presence of peripheral elim ination as their distribution phase occupies the major proportion of their total area under the curve. Changes in the exit site dependent PK parameter s (Vd(ss)) are also mostly significant when k(20) is smaller than k(10). Al though the physiological proccsses that determine drug distribution and tho se affecting peripheral elimination are independent, the two are mathematic ally tied together in the two-compartment model with both central and perip heral elimination. It follows that, as greater importance is given to k(2a) the rare of transfer from the central compartment (k(12)) increases. Howev er, as a result of a proportional increase in the volume of the peripheral compartment, peripheral concentrations remain unchanged whether or not peri pheral elimination is assumed. These findings point out the limitations of compartmental analysis when peripheral elimination cannot be measured direc tly.