Drug-Drug Interactions Associated with Kinase Inhibitors - Pharmacokinetics, Distribution

Plasma Protein Binding

The distribution of a drug following absorption is determined by blood flow and the binding to plasma proteins, including albumin, α-1-acid-glycoprotein (AGP), lipoproteins and immunoglobulins.^1,2 If two highly plasma protein-bound drugs are co-administered, one drug can displace the other from its protein binding site and cause an increased concentration of the unbound drug.¹ The unbound drug is biologically active because it can exert its pharmacological effect, while plasma protein binding limits the activity of the bound drug.²

Drug Displacement from Protein-Binding Sites

Displacement of bound drug from blood components or tissue-binding sites is thought to increase the apparent volume of distribution  of the drug.² However, the effect of drug displacement is difficult to determine because an increase in unbound drug makes more drug available for its biological target and also increases the amount of drug available for elimination.²

Distribution of Tyrosine Kinase Inhibitors

All kinase inhibitors are moderately to highly plasma protein bound and, as such, are susceptible to drug interactions when co-administered with other protein-bound agents.¹ However, the available evidence to support this is low quality.

Clinical Relevance

Drug interactions associated with distribution are not usually clinically relevant, and they are most likely to be the consequence of metabolism rather than changes in plasma binding.³

Next page: More about the metabolism process

References

1. van Leeuwen RW, van Gelder T, Mathijssen RH, Jansman FG. Drug-drug interactions with tyrosine-kinase inhibitors: a clinical perspective. Lancet Oncol 2014; 15: e315-326.
2. Scripture CD, Figg WD. Drug interactions in cancer therapy. Nat Rev Cancer 2006; 6: 546-558.
3. Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002; 71: 115-121.