Linagliptin

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C25H28N8O2
Molecular Weight	472.5422
Optical Activity	( - )
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC#CCN1C(=NC2=C1C(=O)N(CC3=NC4=C(C=CC=C4)C(C)=N3)C(=O)N2C)N5CCC[C@@H](N)C5

InChI

InChIKey=LTXREWYXXSTFRX-QGZVFWFLSA-N

InChI=1S/C25H28N8O2/c1-4-5-13-32-21-22(29-24(32)31-12-8-9-17(26)14-31)30(3)25(35)33(23(21)34)15-20-27-16(2)18-10-6-7-11-19(18)28-20/h6-7,10-11,17H,8-9,12-15,26H2,1-3H3/t17-/m1/s1

HIDE SMILES / InChI

Description
Sources: https://investor.lilly.com/releasedetail2.cfm?ReleaseID=542971
Curator's Comment: description was created based on several sources, including

Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor discovered by Boehringer Ingelheim and being developed as an oral once-daily tablet for the treatment of Type 2 diabetes. Linagliptin was first approved by FDA in 2011 under the trade name Tradjenta as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Linagliptin binds to DPP-4 (an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)) in a reversible manner and thus increases the concentrations of incretin hormones. Linagliptin glucose dependently increases insulin secretion and lowers glucagon secretion, thus resulting in better regulation of glucose homeostasis. Linagliptin binds selectively to DPP-4, and selectively inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Dipeptidyl peptidase IV 37 Target ID: CHEMBL284 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/201280s012lbl.pdf	Inhibitor 8504		1.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Type 2 diabetes mellitus 262 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/201280s012lbl.pdf	Secondary		Approved 8583	TRADJENTA Approved Use Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Has not been studied in combination with insulin. Launch Date 2011

C_max

Value	Dose	Co-administered	Analyte	Population
8.9 nM DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201280lbl.pdf	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:		LINAGLIPTIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
16.4 nM EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/23331248	5 mg 1 times / day steady-state, oral dose: 5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		LINAGLIPTIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
139 nM × h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201280lbl.pdf	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:		LINAGLIPTIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
194 nM × h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/23331248	5 mg 1 times / day steady-state, oral dose: 5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		LINAGLIPTIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
119 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/23331248	5 mg 1 times / day steady-state, oral dose: 5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		LINAGLIPTIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
25% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201280lbl.pdf	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:		LINAGLIPTIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
600 mg single, oral Highest studied dose Dose: 600 mg Route: oral Route: single Dose: 600 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201280lbl.pdf https://pubmed.ncbi.nlm.nih.gov/18812608	healthy, 38.3 years (range: 23-63 years) Health Status: healthy Age Group: 38.3 years (range: 23-63 years) Sex: M Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201280lbl.pdf https://pubmed.ncbi.nlm.nih.gov/18812608	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201280lbl.pdf https://pubmed.ncbi.nlm.nih.gov/18812608

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946 inhibitor 2252 inducer 1087	inhibitor 2438	inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OATP2 4 OCT1 620 CYP2A6 879 CYP2E1 1060 CYP4A11 21 CYP2C8 1057 CYP1A2 2153 CYP2B6 926 CYP2C19 2057 P-gp 1741 BCRP 910 MRP2 499 OCT2 779 OAT4 150 OCTN1 32 OCTN2 71 OAT1 725 OAT3 747	P-gp 2052 BCRP 697 MRP2 252 OCT2 434 OAT4 93 OCTN1 55 OCTN2 59 OATP2 11 OCT1 393 OAT1 395 OAT3 391	CYP1A2 832 CYP2B6 669

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP2C8 1117	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=59, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=201 Page: 38, (ClinPharm) 58, (PMDA in Japanese_I101-1) 78, (PMDA in Japanese_K101-1) 83-85, 201	no [IC50 >10 uM]		no (co-administration study) Comment: Pooled human liver microsomes (paclitaxel 6a-hydroxylation), Coadministration of linagliptin (10 mg QD days 1-12) decreased pioglitazone (CYP2C8 & CYP3A4 substrate, 45 mg QD days 6-12) AUCtau,ss by 5.6% and Cmax,ss by 14.4%. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=59, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=201 Page: 38, (ClinPharm) 58, (PMDA in Japanese_I101-1) 78, (PMDA in Japanese_K101-1) 83-85, 201
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78 Page: 38, (PMDA in Japanese) 78	no [IC50 >100 uM]
CYP2A6 911	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78 Page: 38, (PMDA in Japanese) 78	no [IC50 >100 uM]
CYP2B6 1160	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78 Page: 38, (PMDA in Japanese) 78	no [IC50 >100 uM]
CYP2C19 2141	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78 Page: 38, (PMDA in Japanese) 78	no [IC50 >100 uM]
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78 Page: 38, (PMDA in Japanese) 78	no [IC50 >100 uM]
CYP2E1 1146	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78 Page: 38, (PMDA in Japanese) 78	no [IC50 >100 uM]
CYP4A11 25	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78 Page: 38, (PMDA in Japanese) 78	no [IC50 >100 uM]
BCRP 985	inhibitor 4027 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
CYP1A2 2333	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44 Page: 38.0	no
CYP2B6 1160	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44 Page: 38.0	no
CYP3A4 2633	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44 Page: 38.0	no
MRP2 625	inhibitor 4027 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OAT1 730	inhibitor 4027 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OAT3 749	inhibitor 4027 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OAT4 150	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=59, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OCTN2 71	inhibitor 4027 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OCT2 782	inhibitor 4027 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (ClinPharm) 59, (PMDA in Japanese) 37, 38	no		no (co-administration study) Comment: OCT2-HEK293 cells, Coadministration of linagliptin increased metformin (OCT2 substrate) AUCtau,ss by 0.8% and decreased Cmax,ss by 11.4%. Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (ClinPharm) 59, (PMDA in Japanese) 37, 38
P-gp 1932	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=33, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=59, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: 27, (ClinPharm) 58, (PMDA in Japanese_I101-1) 37, 38, (PMDA in Japanese_K101-1) 92-93, 211	weak [IC50 66.1 uM]		unlikely (co-administration study) Comment: MDR1-LLC-PK cells, MDR1-MDCKII cell monolayers; IC50 = 55 mcM (Caco-2 cells), concentration dependent and saturable inhibitor, Coadministration of ligagliptin increased Digoxin (P-gp substrate) AUCtau,ss by 1.5% and decreased Cmax by 5.8%. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=33, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=59, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: 27, (ClinPharm) 58, (PMDA in Japanese_I101-1) 37, 38, (PMDA in Japanese_K101-1) 92-93, 211
OCTN1 32	inhibitor 4027 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 37, 38	weak [IC50 >100 uM]
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=58, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=204, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=210 Page: 38, (ClinPharm) 57, 58, (PMDA in Japanese_I101-1) 78, (PMDA in Japanese_K101-1) 86-87, 90-91, 204, 210	weak [IC50 >100 uM]		unlikely (co-administration study) Comment: Pooled human liver microsomes (tolbutamide hydroxylation); IC50 = 19.6 mcM (diclofenac 4'-hydroxylation); IC50 = 15.2 mcM, Ki = 8.28 mcM (flurbiprofen 4'-hydroxylation); Coadministration of linagliptin decreased R-warfarin (warfarin, CYP2C9 substrate) AUC0-inf by 1.5% and Cmax 0.3%, and increased S-warfarin AUC0-inf by 3.0% and Cmax by 0.9%. Coadministration of linagliptin decreased glyburide (CYP2C9 substrate) AUC0-inf by 14.3% and Cmax by 13.8%. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=58, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=204, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=210 Page: 38, (ClinPharm) 57, 58, (PMDA in Japanese_I101-1) 78, (PMDA in Japanese_K101-1) 86-87, 90-91, 204, 210
CYP3A4 2633	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=58, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=206 Page: 38, (ClinPharm) 57, (PMDA in Japanese_I101-1) 78, (PMDA in Japanese_K101-1) 88-89, 206-207	weak [Ki 36.3 uM]		weak (co-administration study) Comment: Pooled human liver microsomes (testosterone 6b-hydroxylation, IC50 = 36.3 mcM, Ki = 115 mcM; erythromycin N-demethylation, IC50 = 41.6 mcM), irreversible inhibitior (poor to moderate); Due to the high potency DPP4 inhibition of linagliptin, resulting in clinical Cmax of 20 nM, the potential for in vivo CYP3A4, MAO-B, or CYP2C9 inhibition are minimal at therapeutic exposures. Coadministration of linagliptin increased simvastatin (CYP3A4 substarate) AUCtau,ss by 34.17% and Cmax,ss by 10.01%, and simvastatin acid AUCtau,ss by 33.26% and Cmax,ss by 20.74%. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=58, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=78, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=206 Page: 38, (ClinPharm) 57, (PMDA in Japanese_I101-1) 78, (PMDA in Japanese_K101-1) 88-89, 206-207
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=80 Page: 38, (PMDA in Japanese_I101-1) 80	yes [IC50 15 uM]	CD 1790 1
CYP3A4 2633	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I101_1.pdf#page=80 Page: 38, (PMDA in Japanese_I101-1) 80	yes [IC50 43.2 uM]	CD 1790 1
OCT1 656	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=33, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=200 Page: 27, (PMDA in Japanese_I101-1) 37, 38, (PMDA in Japanese_K101-1) 81-82, 200	yes [IC50 45.2 uM]
OATP2 4	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=33, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: 27, (PMDA in Japanese) 37, 38	yes [IC50 69.7 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
P-gp 2052	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=33, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=59, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=198, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=199 Page: 27, (ClinPharm) 58, 59, (PMDA in Japanese_I101-1) 37, 38, (PMDA in Japanese_K101-1) 73-76, 77-80, 198, 199	moderate [Km 187 uM]	yes (co-administration study) Comment: MDR1-LLC-PK cells, MDR1-MDCKII cell monolayers, Coadministration of ritonavir (potent P-gp and CYP3A4 inhibitor) increased linagliptin AUC0-24 by 101.4% and Cmax by 195.7%., Coadministration of rifampicin (potent P-gp and CYP3A4 inducer) decreased linagliptin AUCtau,ss by 39.5% and Cmax,ss by 43.8%. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=33, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=59, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=198, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=199 Page: 27, (ClinPharm) 58, 59, (PMDA in Japanese_I101-1) 37, 38, (PMDA in Japanese_K101-1) 73-76, 77-80, 198, 199
BCRP 697	substrate 4014 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
MRP2 252	substrate 4014 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OAT1 395	substrate 4014 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OAT3 391	substrate 4014 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OATP2 11	substrate 4014 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OCT1 393	substrate 4014 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OAT4 93	substrate 4014 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 37, 38	yes
OCT2 434	substrate 4014 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 37, 38	yes
OCTN1 55	substrate 4014 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 37, 38	yes
OCTN2 59	substrate 4014 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 37, 38	yes
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=59, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=198, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=199 Page: 38, (ClinPharm) 58, 59, (PMDA in Japanese_K101-1) 73-76, 77-80, 198, 199	yes	yes (co-administration study) Comment: Coadministration of ritonavir (potent P-gp and CYP3A4 inhibitor) increased linagliptin AUC0-24 by 101.4% and Cmax by 195.7%., Coadministration of rifampicin (potent P-gp and CYP3A4 inducer) decreased linagliptin AUCtau,ss by 39.5% and Cmax,ss by 43.8%. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000ClinPharmR.pdf#page=59, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=198, https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_K101_1.pdf#page=199 Page: 38, (ClinPharm) 58, 59, (PMDA in Japanese_K101-1) 73-76, 77-80, 198, 199

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=33 Page: 27.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:68610	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:68610
ChemicalBook	CB71518518	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB71518518
MolPort	MolPort-021-783-260	https://www.molport.com/shop/molecule-link/MolPort-021-783-260
Selleck Chemicals	linagliptin-bi-1356	http://www.selleckchem.com/products/linagliptin-bi-1356.html
ZINC	ZINC000003820029	http://zinc15.docking.org/substances/ZINC000003820029

PubMed

Title	Date	PubMed
		252160946
Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients.	2009 Aug	19476474
Tissue distribution of the novel DPP-4 inhibitor BI 1356 is dominated by saturable binding to its target in rats.	2009 Jul	19562682
Inhibition of dipeptidyl peptidase 4 by BI-1356, a new drug for the treatment of beta-cell failure in type 2 diabetes.	2009 Jun	19426127
Linagliptin, a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes.	2009 Oct	19777398
Incorrect description of mode of excretion of linagliptin.	2010	21701621
The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans.	2010 Apr	20086031
Impact of target-mediated drug disposition on Linagliptin pharmacokinetics and DPP-4 inhibition in type 2 diabetic patients.	2010 Aug	20160157
Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled Type 2 diabetes.	2010 Dec	21059094
Effect of linagliptin (BI 1356) on the steady-state pharmacokinetics of simvastatin.	2010 Jun	20497745
Type 2 diabetes: postprandial hyperglycemia and increased cardiovascular risk.	2010 Mar 24	20448799

Patents

Sample Use Guides

In Vivo Use Guide

The recommended dose of Tradjenta is 5 mg once daily, tablets can be taken with or without food.

Route of Administration: Oral

In Vitro Use Guide

To study dissociation of BI 1356 (linagliptin) from the DPP-4 enzyme Caco-2 cell extract was preincubated with BI 1356 at concentration of 30 nM for, high above the respective Ki value of 1 nM. The enzymatic reaction was started by adding the substrate after a 3000-fold dilution of the preincubation mixture. Enzyme rates in the presence of BI 1356 were measured at different times after dilution (v in relative fluorescence units/seconds × 1000) and corrected for the rate of an uninhibited reaction. koff rate was obtained from a one-phase exponential decay equation fitted to the data points. The calculated koff rate for BI 1356 was 3.0 × 10(–5)/s.

Name

Type

Language

GLYXAMBI COMPONENT LINAGLIPTIN

Preferred Name

English

Linagliptin

Official Name

English

TRIJARDY XR COMPONENT LINAGLIPTIN

Brand Name

English

linagliptin [INN]

Common Name

English

BI-1356

Code

English

8-[(3R)-3-Aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione

Systematic Name

English

LINAGLIPTIN [VANDF]

Common Name

English

(R)-8-(3-Amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione

Systematic Name

English

BS-1356-BS

Code

English

BI1356

Code

English

1H-Purine-2,6-dione, 8-((3R)-3-amino-1-piperidinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-((4-methyl-2-quinazolinyl)methyl)-

Systematic Name

English

Linagliptin [WHO-DD]

Common Name

English

TRAZENTA

Brand Name

English

LINAGLIPTIN [MI]

Common Name

English

1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-

Systematic Name

English

LINAGLIPTIN [USAN]

Common Name

English

BI-1356-BS

Code

English

LINAGLIPTIN [JAN]

Common Name

English

LINAGLIPTIN [ORANGE BOOK]

Common Name

English

BI-1356BS

Code

English

BI 1356

Code

English

TRAJENTA

Brand Name

English

BI 1356 BS

Code

English

LINAGLIPTIN [MART.]

Common Name

English

BS 1356 BS

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C98086