PMID- 34687551
OWN - NLM
STAT- MEDLINE
DCOM- 20220426
LR  - 20220729
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 88
IP  - 4
DP  - 2022 Feb
TI  - Common UGT1A9 polymorphisms do not have a clinically meaningful impact on the 
      apparent oral clearance of dapagliflozin in type 2 diabetes mellitus.
PG  - 1942-1946
LID - 10.1111/bcp.15117 [doi]
AB  - Dapagliflozin is an inhibitor of human renal sodium-glucose cotransporter 2 
      (SGLT2), first approved for the treatment of type 2 diabetes mellitus (T2DM). 
      Dapagliflozin is primarily metabolized by uridine diphosphate 
      glucuronosyltransferase 1A9 (UGT1A9). The effect of UGT1A9 polymorphisms on 
      dapagliflozin apparent oral clearance (CL/F) was studied with dapagliflozin 
      population pharmacokinetic data and UGT1A9 genotype data (I.399C>T, rs2011404, 
      rs6759892, rs7577677, rs4148323, UGT1A9*2 and UGT1A9*3) from a Phase 2 study 
      conducted in subjects with T2DM (n = 187). An analysis of covariance (ANCOVA) 
      model accounting for known covariates influencing dapagliflozin CL/F was applied 
      to these data to quantify the impact of each UGT1A9 polymorphism relative to the 
      wildtype UGT1A9 genotype. The analysis showed that the geometric mean ratios of 
      dapagliflozin CL/F for all of the UGT1A9 polymorphisms studied were within the 
      range of wildtype UGT1A9 CL/F values. Consequently, the polymorphisms of UGT1A9 
      studied had no clinically meaningful impact on the CL/F of dapagliflozin.
CI  - (c) 2021 The Authors. British Journal of Clinical Pharmacology published by John 
      Wiley & Sons Ltd on behalf of British Pharmacological Society.
FAU - Naagaard, M Daniel
AU  - Naagaard MD
AD  - Swarthmore College, Swarthmore, PA, USA.
FAU - Chang, Roy
AU  - Chang R
AD  - Emory University, Atlanta, GA, USA.
FAU - Nagard, Mats
AU  - Nagard M
AUID- ORCID: 0000-0001-9643-1638
AD  - Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and 
      Safety Sciences, R&D Biopharmaceuticals, AstraZeneca, Gaithersburg, MD, USA.
FAU - Tang, Weifeng
AU  - Tang W
AD  - Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and 
      Safety Sciences, R&D Biopharmaceuticals, AstraZeneca, Gaithersburg, MD, USA.
FAU - Boulton, David W
AU  - Boulton DW
AD  - Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and 
      Safety Sciences, R&D Biopharmaceuticals, AstraZeneca, Gaithersburg, MD, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220123
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Benzhydryl Compounds)
RN  - 0 (Glucosides)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Sodium-Glucose Transporter 2 Inhibitors)
RN  - 1ULL0QJ8UC (dapagliflozin)
RN  - EC 2.4.1.17 (Glucuronosyltransferase)
RN  - EC 2.4.1.17 (UDP-Glucuronosyltransferase 1A9)
SB  - IM
MH  - Benzhydryl Compounds
MH  - *Diabetes Mellitus, Type 2/drug therapy/genetics/metabolism
MH  - Glucosides
MH  - Glucuronosyltransferase/genetics/metabolism
MH  - Humans
MH  - Hypoglycemic Agents
MH  - *Sodium-Glucose Transporter 2 Inhibitors/pharmacokinetics
MH  - UDP-Glucuronosyltransferase 1A9
PMC - PMC9305486
OTO - NOTNLM
OT  - UGT1A9
OT  - dapagliflozin
OT  - oral clearance
OT  - polymorphism
OT  - type 2 diabetes mellitus
COIS- M.D.N. and R.C. have no conflicts of interest to report. M.N., W.T. and D.W.B. 
      are employees and shareholders of AstraZeneca.
EDAT- 2021/10/24 06:00
MHDA- 2022/04/27 06:00
PMCR- 2022/01/23
CRDT- 2021/10/23 17:05
PHST- 2021/09/20 00:00 [revised]
PHST- 2021/03/22 00:00 [received]
PHST- 2021/10/07 00:00 [accepted]
PHST- 2021/10/24 06:00 [pubmed]
PHST- 2022/04/27 06:00 [medline]
PHST- 2021/10/23 17:05 [entrez]
PHST- 2022/01/23 00:00 [pmc-release]
AID - BCP15117 [pii]
AID - 10.1111/bcp.15117 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2022 Feb;88(4):1942-1946. doi: 10.1111/bcp.15117. Epub 2022 
      Jan 23.