Impact of genetic deficiencies of P-glycoprotein and breast cancer resistance protein on pharmacokinetics of aripiprazole and dehydroaripiprazole. (October 2014)

• Record Type: Journal Article
• Authors: Nagasaka, Yasuhisa; Sano, Tomokazu; Oda, Kazuo; Kawamura, Akio; Usui, Takashi
• Is Part Of: Xenobiotica. Volume 44:Number 10(2014:Oct.)
• Page Start: 926
• Page End: 932
• Publication Date: 2014-10
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2014.901585
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>1. We investigated how deficiencies in P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) affect the pharmacokinetics of atypical antipsychotics aripiprazole and its active metabolite (dehydroaripiprazole) using normal Friend leukemia virus strain B (FVB) mice, BCRP knockout (Bcrp[−/−]) mice, and P-gp and BCRP triple knockout (Mdr1a/1b[−/−]Bcrp[−/−]) mice.</p> <p>2. While plasma concentrations of aripiprazole and dehydroaripiprazole after oral administration were slightly higher in both Bcrp(−/−) and Mdr1a/1b(−/−)/Bcrp(−/−) mice than in normal FVB mice, the difference was not marked. The increase in absolute bioavailability (<italic>F</italic>) compared with normal mice (approximately 1.3-fold increase) was comparable between Bcrp(−/−) and Mdr1a/1b(−/−)/Bcrp(−/−) mice. This finding suggests that BCRP may be involved in the intestinal absorption of aripiprazole in mice, albeit with minimal contribution to absorption at best.</p> <p>3. In contrast, the brain-to-plasma concentration ratio (<italic>K</italic><sub>p, brain</sub>) for aripiprazole and dehydroaripiprazole after oral administration was significantly higher in Mdr1a/1b(−/−)/Bcrp(−/−) mice than in normal mice, whereas Bcrp(−/−) mice exhibited <italic>K</italic><sub>p, brain</sub> values similar to those in normal mice. In addition, the <italic>K</italic><sub>p, brain</sub> values in Mdr1a/1b(−/−)/Bcrp(−/−) mice were not drastically different from those previously reported in Mdr1a/1b(−/−) mice, suggesting that brain penetration of aripiprazole and dehydroaripiprazole can be affected by P-gp, but with little synergistic effect of BCRP.</p> </abstract>