PMID- 21870203
OWN - NLM
STAT- MEDLINE
DCOM- 20120320
LR  - 20211020
IS  - 1550-7416 (Electronic)
IS  - 1550-7416 (Linking)
VI  - 13
IP  - 4
DP  - 2011 Dec
TI  - Pharmacodynamic model of sodium-glucose transporter 2 (SGLT2) inhibition: 
      implications for quantitative translational pharmacology.
PG  - 576-84
LID - 10.1208/s12248-011-9297-2 [doi]
AB  - Sodium-glucose co-transporter-2 (SGLT2) inhibitors are an emerging class of 
      agents for use in the treatment of type 2 diabetes mellitus (T2DM). Inhibition of 
      SGLT2 leads to improved glycemic control through increased urinary glucose 
      excretion (UGE). In this study, a biologically based 
      pharmacokinetic/pharmacodynamic (PK/PD) model of SGLT2 inhibitor-mediated UGE was 
      developed. The derived model was used to characterize the acute PK/PD 
      relationship of the SGLT2 inhibitor, dapagliflozin, in rats. The quantitative 
      translational pharmacology of dapagliflozin was examined through both prospective 
      simulation and direct modeling of mean literature data obtained for dapagliflozin 
      in healthy subjects. Prospective simulations provided time courses of UGE that 
      were of consistent shape to clinical observations, but were modestly biased 
      toward under prediction. Direct modeling provided an improved characterization of 
      the data and precise parameter estimates which were reasonably consistent with 
      those predicted from preclinical data. Overall, these results indicate that the 
      acute clinical pharmacology of SGLT2 inhibitors in healthy subjects can be 
      reasonably well predicted from preclinical data through rational accounting of 
      species differences in pharmacokinetics, physiology, and SGLT2 pharmacology. 
      Because these data can be generated at the earliest stages of drug discovery, the 
      proposed model is useful in the design and development of novel SGLT2 inhibitors. 
      In addition, this model is expected to serve as a useful foundation for future 
      efforts to understand and predict the effects of SGLT2 inhibition under chronic 
      administration and in other patient populations.
FAU - Maurer, Tristan S
AU  - Maurer TS
AD  - Department of Pharmacokinetics, Pharmacodynamics, and Metabolism, Pfizer Inc., 
      Groton, Connecticut, 06340, USA. tristan.s.maurer@pfizer.com
FAU - Ghosh, Avijit
AU  - Ghosh A
FAU - Haddish-Berhane, Nahor
AU  - Haddish-Berhane N
FAU - Sawant-Basak, Aarti
AU  - Sawant-Basak A
FAU - Boustany-Kari, Carine M
AU  - Boustany-Kari CM
FAU - She, Li
AU  - She L
FAU - Leininger, Michael T
AU  - Leininger MT
FAU - Zhu, Tong
AU  - Zhu T
FAU - Tugnait, Meera
AU  - Tugnait M
FAU - Yang, Xin
AU  - Yang X
FAU - Kimoto, Emi
AU  - Kimoto E
FAU - Mascitti, Vincent
AU  - Mascitti V
FAU - Robinson, Ralph P
AU  - Robinson RP
LA  - eng
PT  - Journal Article
DEP - 20110826
PL  - United States
TA  - AAPS J
JT  - The AAPS journal
JID - 101223209
RN  - 0 (Benzhydryl Compounds)
RN  - 0 (Glucosides)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (SLC5A2 protein, human)
RN  - 0 (Sodium-Glucose Transporter 2)
RN  - 0 (Sodium-Glucose Transporter 2 Inhibitors)
RN  - 1ULL0QJ8UC (dapagliflozin)
SB  - IM
MH  - Animals
MH  - Benzhydryl Compounds
MH  - Diabetes Mellitus, Type 2/drug therapy
MH  - Glucosides/pharmacokinetics/pharmacology
MH  - Humans
MH  - Hypoglycemic Agents/*pharmacology/therapeutic use
MH  - *Models, Biological
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Sodium-Glucose Transporter 2
MH  - *Sodium-Glucose Transporter 2 Inhibitors
PMC - PMC3231856
EDAT- 2011/08/27 06:00
MHDA- 2012/03/21 06:00
PMCR- 2012/08/26
CRDT- 2011/08/27 06:00
PHST- 2011/04/01 00:00 [received]
PHST- 2011/08/12 00:00 [accepted]
PHST- 2011/08/27 06:00 [entrez]
PHST- 2011/08/27 06:00 [pubmed]
PHST- 2012/03/21 06:00 [medline]
PHST- 2012/08/26 00:00 [pmc-release]
AID - 9297 [pii]
AID - 10.1208/s12248-011-9297-2 [doi]
PST - ppublish
SO  - AAPS J. 2011 Dec;13(4):576-84. doi: 10.1208/s12248-011-9297-2. Epub 2011 Aug 26.