Application of Kirchhoff’s Laws to pharmacologic and pharmacokinetic analyses

Significance Statement I. Introduction II.The basic concepts: Pharmacokinetics vs chemistry III.Kirchhoff's Laws as applied to deriving coefficients of proportionality: Total clearance and the total rate constant of elimination A. Adapted Kirchhoff's Laws definitions 1. Rate-defining processes 2. Parallel and in-series processes B. The advantages of the adapted Kirchhoff's Laws derivations IV.Deriving renal and hepatic clearance relationships using Kirchhoff's Laws A. Renal clearance B. Hepatic clearance 1.When hepatocellular transport is not a rate-defining process 2. When hepatocellular transport is clinically relevant 3.There is no clinical relevance to the mechanistic models of hepatic elimination V.The utility of Kirchhoff's Laws in deriving chemical rate of reaction relationships VI.Application of Kirchhoff's Laws to explain previously considered anomalous experimental data following slow drug input processes A. Deriving the equations to explain systemic bioavailability measures greater than unity 1.The present approach 2. The Kirchhoff's Laws approach 3. MRT concepts following oral absorption 4. Converting rate constants to clearances 5. Measures of renal clearance support the Kirchhoff's Laws approach VII.What Our published Kirchhoff's Laws papers explain VIII.Ongoing discoveries and further applications of Kirchhoff's Laws A. Increased response effects for slow-release pharmaceutical formulations B. The potential of developing high hepatic clearance drugs via controlled release C.The application of Kirchhoff's Laws to saturable, Michaelis-Menten, pharmacokinetics D. Explaining the decrease in clearance for high hepatic extraction ratio drugs as a function of increasing zero-order infusion times IX.