PMID- 23073734
OWN - NLM
STAT- MEDLINE
DCOM- 20130625
LR  - 20181202
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Linking)
VI  - 41
IP  - 1
DP  - 2013 Jan
TI  - Evaluation and prediction of potential drug-drug interactions of linagliptin 
      using in vitro cell culture methods.
PG  - 149-58
LID - 10.1124/dmd.112.048470 [doi]
AB  - Linagliptin is a highly potent dipeptidyl peptidase-4 (DPP-4) inhibitor approved 
      for the treatment of type 2 diabetes. Unlike other DPP-4 inhibitors, linagliptin 
      is cleared primarily via the bile and gut. We used a panel of stably and 
      transiently transfected cell lines to elucidate the carrier-mediated transport 
      processes that are involved in linagliptin disposition in vivo and to assess the 
      potential for drug-drug interactions (DDIs). Our results demonstrate that 
      linagliptin is a substrate of organic cation transporter 2 (OCT2) and 
      P-glycoprotein (P-gp) but not of organic anion-transporting polypeptide 1B1 and 
      1B3; organic anion transporter 1, 3, and 4; OCT1; or organic cation/carnitine 
      transporter 1 and 2, suggesting that OCT2 and P-gp play a role in the disposition 
      of linagliptin in vivo. Linagliptin inhibits transcellular transport of digoxin 
      by P-gp with an apparent IC(50) of 66.1 muM, but it did not inhibit activity of 
      multidrug resistance-associated protein 2 and breast cancer resistance protein as 
      represented by transport of probe substrate into membrane vesicles from 
      respective transporter-expressing cells. In addition, the inhibitory effect of 
      linagliptin on major solute carrier transporter isoforms was investigated. 
      Linagliptin showed inhibitory potency against only OCT1 and OCT2 out of all major 
      solute carrier transporter isoforms examined, and those inhibition potencies, 
      evaluated using three different in vitro probe substrates, were 
      substrate-specific. Considering the low therapeutic plasma concentration of 
      linagliptin, our data clearly suggest a very low risk for transporter-mediated 
      DDIs with comedications in clinical practice.
FAU - Ishiguro, Naoki
AU  - Ishiguro N
AD  - Nippon Boehringer Ingelheim Co., Ltd., 6-7-5 Minatojima-Minamimachi, Chuo-ku, 
      Kobe, Hyogo, Japan 650-0047. naoki.ishiguro@boehringer-ingelheim.com
FAU - Shimizu, Hidetada
AU  - Shimizu H
FAU - Kishimoto, Wataru
AU  - Kishimoto W
FAU - Ebner, Thomas
AU  - Ebner T
FAU - Schaefer, Olaf
AU  - Schaefer O
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121016
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (DNA Primers)
RN  - 0 (Dipeptidyl-Peptidase IV Inhibitors)
RN  - 0 (Purines)
RN  - 0 (Quinazolines)
RN  - 3X29ZEJ4R2 (Linagliptin)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
MH  - ATP-Binding Cassette Transporters/antagonists & inhibitors
MH  - Animals
MH  - Base Sequence
MH  - DNA Primers
MH  - Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics/*pharmacology
MH  - Drug Evaluation, Preclinical
MH  - *Drug Interactions
MH  - HEK293 Cells
MH  - Humans
MH  - In Vitro Techniques
MH  - LLC-PK1 Cells
MH  - Linagliptin
MH  - Purines/pharmacokinetics/*pharmacology
MH  - Quinazolines/pharmacokinetics/*pharmacology
MH  - Swine
EDAT- 2012/10/18 06:00
MHDA- 2013/06/26 06:00
CRDT- 2012/10/18 06:00
PHST- 2012/10/18 06:00 [entrez]
PHST- 2012/10/18 06:00 [pubmed]
PHST- 2013/06/26 06:00 [medline]
AID - dmd.112.048470 [pii]
AID - 10.1124/dmd.112.048470 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2013 Jan;41(1):149-58. doi: 10.1124/dmd.112.048470. Epub 2012 
      Oct 16.