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Chemical Compound Review:

Gemcabene 6-(5-carboxy-5-methyl- hexoxy)-2,2-dimethyl...

Synonyms: AG-E-33024, AC1L4IHZ, PD-72953, CTK4D8457, PD 72953, ...

Bauman, J.N. et al., Bisgaier, C.L. et al., Mandema, J.W. et al., Bays, H.E. et al.

Mandema, Hermann, Wang, Sheiner, Milad, Bakker-Arkema, Hartman, Bays, McKenney, Dujovne, Schrott, Zema, Nyberg, MacDougall, Bauman, Goosen, Tugnait, Peterkin, Hurst, Menning, Milad, Court, Williams,

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Psychiatry related information on Gemcabene

The purpose of this study was to evaluate the value of model-based, quantitative decision making during the development of gemcabene, a novel lipid-altering agent [1].

High impact information on Gemcabene

At 100 mg/kg, PD 72953 further elevated HDL-cholesterol to 232% of control levels, and was associated with increased HDL size and plasma apoE (169% of control), despite no change in hepatic apoE mRNA [2].
Whole animal studies, transient transfection studies in HepG2 cells, and chimeric receptor studies in kidney 293 cells suggest that PD 72953 is a ligand for the peroxisomal proliferation activated receptor alpha (PPARalpha), and PPARgamma [2].
In conclusion, using the three independent experimental approaches typically used for cytochrome P450 reaction phenotyping, UGT2B7 is the major enzyme contributing to gemcabene glucuronidation in human liver microsomes [3].
Glucuronidation of gemcabene was catalyzed by recombinant UGT1A3, recombinant UGT2B7, and recombinant UGT2B17, as well as by human liver microsomes (HLM) [3].
Udp-glucuronosyltransferase 2b7 is the major enzyme responsible for gemcabene glucuronidation in human liver microsomes [3].

Biological context of Gemcabene

Gemcabene glucuronidation in recombinant UGTs and HLM followed non-Michaelis-Menten kinetics consistent with homotropic activation, but pharmacokinetics in humans were linear over the dose range tested (total plasma C(max), 0.06-0.88 mM) [3].

Associations of Gemcabene with other chemical compounds

Overall, PD 72953 may act through a peroxisomal proliferation activated receptor and result in plasma triglycerides and apoB-containing lipoprotein reduction, while also raising HDL cholesterol [2].
Reaction rates for gemcabene glucuronidation from a human liver bank correlated well (r(2)=0.722, P<0.0001; n=24) with rates of glucuronidation of the UGT2B7 probe substrate 3'-azido-3'-deoxythymidine [3].
S-Flurbiprofen was identified as a more selective inhibitor of recombinant UGT2B7-catalyzed gemcabene glucuronidation (>23-fold lower IC(50)) when compared with recombinant UGT1A3- or recombinant UGT2B17-catalyzed gemcabene glucuronidation [3].

Gene context of Gemcabene

In the TG >/=200 mg/dl stratum, gemcabene significantly increased serum HDL cholesterol by 18% with corresponding significant increases of 6% in both apolipoprotein A-I and A-II levels at the 150-mg dose [4].
The modeling greatly enhanced the understanding of the clinical profile of gemcabene when given alone or in combination with a statin [1].

References

Model-based development of gemcabene, a new lipid-altering agent. Mandema, J.W., Hermann, D., Wang, W., Sheiner, T., Milad, M., Bakker-Arkema, R., Hartman, D. The AAPS journal [electronic resource]. (2005) [Pubmed]
A novel compound that elevates high density lipoprotein and activates the peroxisome proliferator activated receptor. Bisgaier, C.L., Essenburg, A.D., Barnett, B.C., Auerbach, B.J., Haubenwallner, S., Leff, T., White, A.D., Creger, P., Pape, M.E., Rea, T.J., Newton, R.S. J. Lipid Res. (1998) [Pubmed]
Udp-glucuronosyltransferase 2b7 is the major enzyme responsible for gemcabene glucuronidation in human liver microsomes. Bauman, J.N., Goosen, T.C., Tugnait, M., Peterkin, V., Hurst, S.I., Menning, L.C., Milad, M., Court, M.H., Williams, J.A. Drug Metab. Dispos. (2005) [Pubmed]
Effectiveness and tolerability of a new lipid-altering agent, gemcabene, in patients with low levels of high-density lipoprotein cholesterol. Bays, H.E., McKenney, J.M., Dujovne, C.A., Schrott, H.G., Zema, M.J., Nyberg, J., MacDougall, D.E. Am. J. Cardiol. (2003) [Pubmed]

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