Quantitative prediction of in vivo drug-drug interactions from in vitro data based on physiological pharmacokinetics: use of maximum unbound concentration of inhibitor at the inlet to the liver

Pharm Res. 2000 Mar;17(3):336-43. doi: 10.1023/a:1007509324428.


Purpose: To assess the degree to which the maximum unbound concentration of inhibitor at the inlet to the liver (I(inlet,u,max), used in the prediction of drug-drug interactions, overestimates the unbound concentration in the liver.

Methods: The estimated value of I(inlet,u,max) was compared with the unbound concentrations in systemic blood, liver, and inlet to the liver, obtained in a simulation study based on a physiological flow model. As an example, a tolbutamide/sulfaphenazole interaction was predicted taking the plasma concentration profile of the inhibitor into consideration.

Results: The value of I(inlet,u,max) differed from the concentration in each compartment, depending on the intrinsic metabolic clearance in the liver, first-order absorption rate constant, non-hepatic clearance and liver-to-blood concentration ratio (Kp) of the inhibitor. The AUC of tolbutamide was predicted to increase 4-fold when co-administered with sulfaphenazole, which agreed well with in vivo observations and was comparable with the predictions based on a fixed value of I(inlet,u,max). The blood concentration of tolbutamide was predicted to increase when it was co-administered with as little as 1/100 of the clinical dose of sulfaphenazole.

Conclusions: Although I(inlet,u,max) overestimated the unbound concentration in the liver, the tolbutamide/sulfaphenazole interaction could be successfully predicted by using a fixed value of I(inlet,u,max) indicating that the unbound concentration of sulfaphenazole in the liver after its clinical dose is by far larger than the concentration to inhibit CYP2C9-mediated metabolism and that care should be taken when it is co-administered with drugs that are substrates of CYP2C9.

MeSH terms

  • Animals
  • Anti-Infective Agents / pharmacokinetics*
  • Aryl Hydrocarbon Hydroxylases*
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 Enzyme Inhibitors
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Humans
  • Hypoglycemic Agents / pharmacokinetics*
  • Liver / drug effects*
  • Liver / enzymology
  • Models, Biological
  • Predictive Value of Tests
  • Steroid 16-alpha-Hydroxylase*
  • Steroid Hydroxylases / antagonists & inhibitors
  • Sulfaphenazole / pharmacokinetics*
  • Tolbutamide / pharmacokinetics*


  • Anti-Infective Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Hypoglycemic Agents
  • Sulfaphenazole
  • Tolbutamide
  • Steroid Hydroxylases
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • Steroid 16-alpha-Hydroxylase