LINAGLIPTIN

Details

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

SHOW SMILES / InChI

Structure Search

SMILES

CC#CCN1C(=NC2=C1C(=O)N(CC3=NC4=CC=CC=C4C(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 36 Target ID: CHEMBL284 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/201280s012lbl.pdf	Inhibitor 8146		1.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Type 2 diabetes mellitus 255 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/201280s012lbl.pdf	Secondary		Approved 8307	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 1.30429446E12

C_max

Value	Dose	Co-administered	Analyte	Population
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
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

AUC

Value	Dose	Co-administered	Analyte	Population
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
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

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) n = 6 Health Status: healthy Age Group: 38.3 years (range: 23-63 years) Sex: M Population Size: 6 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 1670 inhibitor 1532 inducer 753	inhibitor 1695	inhibitor 1789	inhibitor 1570

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OATP2 4 OCT1 498 CYP2A6 670 CYP2E1 846 CYP4A11 21 CYP2C8 869 CYP1A2 1463 CYP2B6 770 CYP2C19 1410 P-gp 1401 BCRP 678 MRP2 363 OCT2 630 OAT4 145 OCTN1 29 OCTN2 66 OAT1 584 OAT3 625	P-gp 1491 BCRP 545 MRP2 196 OCT2 336 OAT4 76 OCTN1 47 OCTN2 50 OATP2 6 OCT1 317 OAT1 314 OAT3 328	CYP1A2 671 CYP2B6 521

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP2C8 923	inhibitor 3185 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 1620	inhibitor 3185 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 702	inhibitor 3185 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 946	inhibitor 3185 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 1484	inhibitor 3185 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 1826	inhibitor 3185 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 929	inhibitor 3185 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 3185 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 751	inhibitor 3185 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
CYP1A2 1620	inducer 1515 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44 Page: 38.0	no
CYP2B6 946	inducer 1515 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44 Page: 38.0	no
CYP3A4 1857	inducer 1515 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201280Orig1s000PharmR.pdf#page=44 Page: 38.0	no
MRP2 452	inhibitor 3185 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OAT1 588	inhibitor 3185 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OAT3 627	inhibitor 3185 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OAT4 145	inhibitor 3185 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 3185 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OCT2 631	inhibitor 3185 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 1588	inhibitor 3185 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 29	inhibitor 3185 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 1747	inhibitor 3185 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 1857	inhibitor 3185 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 1747	inhibitor 3185 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 1857	inhibitor 3185 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 513	inhibitor 3185 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 3185 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 1491	substrate 3264 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 545	substrate 3264 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
MRP2 196	substrate 3264 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OAT1 314	substrate 3264 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OAT3 328	substrate 3264 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OATP2 6	substrate 3264 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OCT1 317	substrate 3264 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 38	no
OAT4 76	substrate 3264 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 37, 38	yes
OCT2 336	substrate 3264 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 37, 38	yes
OCTN1 47	substrate 3264 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 37, 38	yes
OCTN2 50	substrate 3264 Sources: https://www.pmda.go.jp/drugs/2011/P201100128/530353000_22300AMX00605_I100_1.pdf#page=38 Page: (PMDA in Japanese) 37, 38	yes
CYP3A4 1670	substrate 3264 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 1603	inhibitor 1584 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
8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes.	2007 Dec 27	18052023
Evaluation of the potential for steady-state pharmacokinetic and pharmacodynamic interactions between the DPP-4 inhibitor linagliptin and metformin in healthy subjects.	2009 Aug	19552619
Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients.	2009 Aug	19476474
Chronic treatment with the dipeptidyl peptidase-4 inhibitor BI 1356 [(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] increases basal glucagon-like peptide-1 and improves glycemic control in diabetic rodent models.	2009 Feb	18971371
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
Dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes: safety, tolerability, and efficacy.	2010	21701614
The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans.	2010 Apr	20086031
Pharmacokinetics of dipeptidylpeptidase-4 inhibitors.	2010 Aug	20590741
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
Pharmacokinetics and pharmacodynamics of single rising intravenous doses (0.5 mg-10 mg) and determination of absolute bioavailability of the dipeptidyl peptidase-4 inhibitor linagliptin (BI 1356) in healthy male subjects.	2010 Dec	21053992
Linagliptin, a xanthine-based dipeptidyl peptidase-4 inhibitor with an unusual profile for the treatment of type 2 diabetes.	2010 Jan	19947894
The evolving place of incretin-based therapies in type 2 diabetes.	2010 Jul	20130920
Linagliptin, a dipeptidyl peptidase-4 inhibitor in development for the treatment of type 2 diabetes mellitus: a Phase I, randomized, double-blind, placebo-controlled trial of single and multiple escalating doses in healthy adult male Japanese subjects.	2010 Jun	20637971
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
Chronic administration of DSP-7238, a novel, potent, specific and substrate-selective DPP IV inhibitor, improves glycaemic control and beta-cell damage in diabetic mice.	2010 May	20415690
New treatments in the management of type 2 diabetes: a critical appraisal of saxagliptin.	2010 May 10	21437082
DPP-4 inhibitors: what may be the clinical differentiators?	2010 Nov	20708812
Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase-4 inhibitor linagliptin and pioglitazone in healthy volunteers.	2010 Oct	20875371
Dipeptidylpeptidase-4 inhibitors (gliptins): focus on drug-drug interactions.	2010 Sep	20690781
The dipeptidyl peptidase-4 inhibitor linagliptin exhibits time- and dose-dependent localization in kidney, liver, and intestine after intravenous dosing: results from high resolution autoradiography in rats.	2010 Sep	20538719
Exenatide once weekly: clinical outcomes and patient satisfaction.	2010 Sep 7	20859458
Effects of DPP-4 inhibitors on the heart in a rat model of uremic cardiomyopathy.	2011	22125632
Linagliptin, a dipeptidyl peptidase-4 inhibitor with a unique pharmacological profile, and efficacy in a broad range of patients with type 2 diabetes.	2012 Jan	22149370

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

LINAGLIPTIN

Official Name

English

TRIJARDY XR COMPONENT LINAGLIPTIN

Brand Name

English

linagliptin [INN]

Common Name

English

GLYXAMBI COMPONENT LINAGLIPTIN

Brand 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

LINAGLIPTIN COMPONENT OF JENTADUETO

Common Name

English

BS-1356-BS

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

LINAGLIPTIN COMPONENT OF TRIJARDY XR

Brand 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

LINAGLIPTIN COMPONENT OF GLYXAMBI

Brand Name

English

JENTADUETO COMPONENT OF LINAGLIPTIN

Common Name

English

BS 1356 BS

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C98086