The role of unbound drug in pharmacokinetics/pharmacodynamics and in therapy.
The evolution of research on drug protein binding is discussed with the unbound concentration (Cu) and the unbound fraction (fu) as protagonists. Particular attention is paid to the mechanisms via which alterations in binding affect the pharmacokinetics (PK) and the effect, or independently the pharmacodynamics (PD). Apart from albumin, the important alpha-acid glycoprotein (AGP), as well as specific drug classes and applications in the clinic and development (routine monitoring, cancer and HIV therapy, allometry) are addressed. The flaws with the classical method of indirectly calculating the Cu or the unbound PK/PD parameters, based on the fu in vitro, are related to the intrinsic complexity and variability in the outcomes. Increased focus is urged on directly estimating the unbound PK/PD and also on using population statistical methods.
Calvo
Rosario
R
Department of Pharmacology, Faculty of Medicine, University of the Basque Country, Leioa, Vizcaya, Spain.
Lukas
John C
JC
Rodriguez
Monica
M
Leal
Nerea
N
Suarez
Elena
E
D000818:Animals; D044966:Anti-Retroviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001798:Blood Proteins / Q000378:metabolism*; D016903:Drug Monitoring / Q000379:methods; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D023421:Models, Animal; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009961:Orosomucoid / Q000378:metabolism; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism; D013045:Species Specificity
D044966:Anti-Retroviral Agents; D000970:Antineoplastic Agents; D001798:Blood Proteins; D009961:Orosomucoid; D012709:Serum Albumin