+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

HERG potency estimates based upon dose solution analysis: What have we learned?

HERG potency estimates based upon dose solution analysis: What have we learned?

Journal of Pharmacological and Toxicological Methods 64(3): 251-257

Measurement of drug-induced inhibition of potassium current flow through the hERG channel is used to determine potency at the channel, which is used as an in vitro risk assessment for QTc interval prolongation in vivo. In the hERG assay, test solutions of varying strength are prepared to construct a concentration-response curve based upon the nominal drug concentration (NOM). Dose-solution analysis (DSA) is an analytical approach to confirm the test concentration achieved in an in vitro assay (Herron, Towers, & Templeton, 2004), and can be included as a component of hERG channel study to confirm drug concentration in the assay buffer to determine potency using the "actual" drug level in solution (ACT). Thus, DSA could be helpful in confirming test article concentrations. This study examined whether inclusion of DSA improved the accuracy of potency estimates based upon the ACT compared to the NOM concentration during hERG voltage clamp assays (non-GLP) for 99 diverse agents. We examined the correlation of hERG IC(50) derived from NOM with hERG IC(50) derived from ACT, and analyzed potential mechanisms of deviation between ACT and NOM potency values, including solubility, cLogP, PKa, and molecular weights. Seventy-four (74) of 99 agents (73.7%) had NOM- and ACT-derived IC(50) values within 3-fold, 87 of 99 (87.8%) had an IC(50) ratio within 10-fold, and 12 (12.1%) had a >10-fold difference in their NOM IC(50) and ACT IC(50) values. On average, these 12 compounds had less soluble, more lipophilic (high cLogP values), and more basic characters (high pKa values). Our investigation indicated that DSA did not alter hERG potency estimation for the majority of compounds in this dataset, i.e., DSA confirmed the NOM concentration within 3-fold. For poorly soluble agents or agents with high cLogP and pKa values, however, DSA did not clarify or improve hERG potency estimates.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 036186486

Download citation: RISBibTeXText

PMID: 21888984

DOI: 10.1016/j.vascn.2011.08.004

Related references

Molecular determinants of HERG blockade by propafenone Drug trapping of a low potency voltage-dependent HERG blocker. Biophysical Journal 84(2 Part 2): 544a, 2003

Stereoselective Blockage of Quinidine and Quinine in the hERG Channel and the Effect of Their Rescue Potency on Drug-Induced hERG Trafficking Defect. International Journal of Molecular Sciences 17(10):, 2016

Differentiation of ROMK potency from hERG potency in the phenacetyl piperazine series through heterocycle incorporation. Bioorganic and Medicinal Chemistry Letters 26(9): 2339-2343, 2016

The reliability of graphic estimates of relative potency from dose-per cent effect curves. Journal of Pharmacology and Experimental Therapeutics 108(1): 18-25, 1953

Comparison of in vitro and in vivo clastogenic potency based on benchmark dose analysis of flow cytometric micronucleus data. Mutagenesis 31(3): 277-285, 2016

Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugs' cardiotoxic properties. Journal of Applied Toxicology 29(3): 183-206, 2009

Estimates of cancer potency of 2,3,7,8-tetrachlorodibenzo(p)dioxin using linear and nonlinear dose-response modeling and toxicokinetics. Toxicological Sciences 112(2): 490-506, 2009

Marijuana: dose-response effects on pulse rate, subjective estimates of potency, pleasantness, and recognition memory. Pharmacology 15(3): 268-275, 1977

Novel 4,4-disubstituted piperidine-based C-C chemokine receptor-5 inhibitors with high potency against human immunodeficiency virus-1 and an improved human ether-a-go-go related gene (hERG) profile. Journal of Medicinal Chemistry 54(11): 3756-3767, 2011

Moving from external exposure concentration to internal dose: duration extrapolation based on physiologically based pharmacokinetic derived estimates of internal dose. Journal of Toxicology and Environmental Health. Part A 68(11-12): 927-950, 2005

Derivation and application of relative potency estimates based on in vitro bioassay results. Environmental Toxicology and Chemistry 19(11): 2835-2843, 2000

Updated cancer potency assessment for benzene based on new exposure estimates for the pliofilm cohort. Abstracts of Papers American Chemical Society 204(1-2): ENVR 74, 1992

Considerations on absorbed dose estimates based on different beta-dose point kernels in internal dosimetry. Radioisotopes 44(10): 687-692, 1995

Power and uncertainty analysis of epidemiological studies of radiation-related disease risk in which dose estimates are based on a complex dosimetry system: Some observations. Radiation Research 160(4): 408-417, 2003