Genetic variations of orosomucoid genes associated with serum alpha‐1‐acid glycoprotein level and the pharmacokinetics of paclitaxel in Japanese cancer

Alpha‐1‐acid glycoprotein (AGP) encoded by orosomucoid genes (ORM1 and ORM2) is an acute‐phase response protein and functions as a drug‐binding protein that affects pharmacokinetics (PK)/pharmacodynamics of binding drugs. To explore the effects of genetic variations of ORMs and a role of AGP on paclitaxel (PTX) therapy, we analyzed the duplication and genetic variations/haplotypes of ORMs in 165 Japanese cancer patients and then investigated their associations with serum AGP levels and the PK parameters of PTX. No effects of ORM duplications on serum AGP levels at baseline or PK of PTX were observed, but close associations of ORM1 −559T > A with the increases of AGP levels and area under the curve (AUC) of PTX metabolites were detected. In addition, a significant correlation between the serum AGP level and the AUCs of PTX metabolites was observed, suggesting that AGP may function as a carrier of PTX from the blood into the liver via putative receptors. This study provided useful information on the possible clinical importance of ORM genetic polymorphisms and a novel role of AGP in PTX therapy. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4546-4559, 2011