Unmasking the Role of Uptake Transporters for Digoxin Uptake Across the Barriers of the Central Nervous System in Rat

Journal of Central Nervous System Disease

Original Research

Sandhya Mandlekar¹  Vishwanath Kurawattimath²  Srikanth K Sridhar²  Shashyendra Singh Gautam²  TV Radhakrishna Mullapudi²  T Thanga Mariappan²  Kunal S Taskar³  Punit Marathe⁴  Raja Reddy Kallem⁵ 

[1] Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb Research & Development Center (BBRC), Bristol-Myers Squibb India Ltd, Bangalore, India;Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb Research & Development Center (BBRC), Syngene International Limited, Bangalore, India;Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb Research & Development Center (BBRC), Syngene International Limited, Bangalore, India;Mechanistic Safety and Disposition, IVIVT, GlaxoSmithKline, Ware, UK;Pharmaceutical Candidate Optimization, Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Princeton, NJ, USA;School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, USA;

关键词: Digoxin;    P-glycoprotein;    organic anion transporting polypeptide;    blood-brain barrier;    blood-cerebrospinal fluid barrier;    blood-spinal cord barrier;    CNS;   

DOI  :  10.1177/1179573517693596

 received in 2016-09-27, accepted in 2017-01-22,  发布年份 2017

来源: Sage Journals

【 摘 要 】

The role of uptake transporter (organic anion–transporting polypeptide [Oatp]) in the disposition of a P-glycoprotein (P-gp) substrate (digoxin) at the barriers of central nervous system, namely, the blood-brain barrier (BBB), blood-spinal cord barrier (BSCB), and brain-cerebrospinal fluid barrier (BCSFB), was studied using rat as a preclinical species. In vivo chemical inhibition of P-gp and Oatp was achieved using elacridar and rifampicin, respectively. Our findings show that (1) digoxin had a low brain-to-plasma concentration ratio (B/P) (0.07) in rat; (2) in the presence of elacridar, the B/P of digoxin increased by about 12-fold; (3) rifampicin administration alone did not change the digoxin B/P significantly when compared with digoxin B/P alone; (4) rifampicin administration along with elacridar resulted only in 6-fold increase in the B/P of digoxin; (5) similar fold changes and trends were seen with the spinal cord-to-plasma concentration ratio of digoxin, indicating the similarity between BBB and the BSCB; and (6) unlike BBB and BSCB, the presence of rifampicin further increased the cerebrospinal fluid-to-plasma concentration ratio (CSF/P) for digoxin, suggesting a differential orientation of the uptake transporters at the BCSFB (CSF to blood) compared with the BBB (blood to brain). The observations for digoxin uptake, at least at the BBB and the BSCB, advocate the importance of uptake transporters (Oatps). However, the activity of such uptake transporters became evident only after inhibition of the efflux transporter (P-gp).

【 授权许可】

CC BY-NC   
© The Author(s) 2017

【 图 表 】

Figure 5.