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The problem of assessing the value of mathematical models in physiology and medicine is considered. The role of validation within the modeling process is clearly defined. An appropriate vocabulary and validation procedures to be adopted are outlined for simple and complex models, with these two classes defined operationally on the basis of theoretical identifiability. Some examples illustrating these validation procedures are briefly discussed. It is shown that simple and complex models each have a role both in physiology and clinical application when properly validated.

A linear compartmental model has been developed for the in vivo metabolism of glycoproteins. The model is applied to the interpretation of dynamic data from the rat on agalactoorosomucoid (AGOR), an N-acetylglucosamine (GlcNAc-)-terminated glycoprotein, and three neoglycoproteins terminating in mannose [mannose36-bovine serum albumin (Man-BSA)] or glucose [maltose29-BSA (Mal29-BSA) and maltose8-BSA (Mal8-BSA)]. All of these proteins are taken up by the Man/GlcNAc receptor on hepatic sinusoidal cells. The rate of uptake was found to be determined by sugar type (Man-BSA, 0.78 min-1 greater than Mal29-BSA, 0.13 min-1), sugar density (Mal29-BSA greater than Mal8-BSA), and the geometry of the sugar display (AGOR, 0.51 min-1 greater than Mal29-BSA). Intracellular transport from the cell membrane to the lysosomes was slower for Man-BSA (approximately 3 min) than for the other ligands (approximately 0 min), suggesting that receptor-ligand uncoupling was slower for Man-BSA for which the receptor had the highest affinity or that extralysosomal catabolism of the other ligands occurred. Catabolism was also determined by the carbohydrate moiety of the ligand; it was greater for Mal29-BSA and Mal8-BSA (greater than or equal to 0.8 min-1) than for Man-BSA (0.27 min-1), and AGOR, with a complex oligosaccharide, was most resistant to degradation (0.14 min-1). An understanding of these structural features of glycoproteins that influence hepatic uptake, transport, and catabolism will be of value in drug targeting and for enzyme replacement in lysosomal storage disorders.(ABSTRACT TRUNCATED AT 250 WORDS)