Notes on the Use of Kirchhoff’s Laws in Pharmacokinetics

Recent publications by Benet and coworkers, Korzekwa and Nagar, and Rowland et al. signal disagreement regarding the use of Kirchhoff’s laws in combining pharmacokinetic parameters, especially clearances and rate constants. Here, it is pointed out that Kirchhoff’s laws as applied to pharmacokinetics simply assert that concentrations are well defined and that molar or mass balances hold. The real issue is how to combine parameters for clearance processes in sequence, which may be reversible, irreversible, or even active in either or both directions. It is also demonstrated that Kirchhoff’s laws cannot be used to resolve contradictory results observed in liver transport and clearance. Finally, a simple argument is provided relating nonlinear clearance to apparently anomalous bioavailability observations. Graphical Abstract: [Figure not available: see fulltext.].