Merck
  • Home
  • Search Results
  • Translating clinical findings into knowledge in drug safety evaluation--drug induced liver injury prediction system (DILIps).

Translating clinical findings into knowledge in drug safety evaluation--drug induced liver injury prediction system (DILIps).

PLoS computational biology (2011-12-24)
Zhichao Liu, Qiang Shi, Don Ding, Reagan Kelly, Hong Fang, Weida Tong
ABSTRACT

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Sodium chloride physiological solution, BioUltra, tablet
Sigma-Aldrich
Ammonium chloride, ReagentPlus®, ≥99.5%
Sigma-Aldrich
Acetic acid, glacial, puriss. p.a., ACS reagent, reag. ISO, reag. Ph. Eur., ≥99.8%
Sigma-Aldrich
Acetic acid, glacial, puriss., meets analytical specification of Ph. Eur., BP, USP, FCC, 99.8-100.5%
Sigma-Aldrich
Sodium bicarbonate, puriss. p.a., ACS reagent, reag. Ph. Eur., ≥99.7%
Sigma-Aldrich
Potassium chloride, puriss. p.a., reag. ISO, reag. Ph. Eur., 99.5-100.5%
Sigma-Aldrich
Acetic acid solution, suitable for HPLC
Sigma-Aldrich
Sodium acetate, puriss. p.a., ACS reagent, reag. Ph. Eur., anhydrous
Sigma-Aldrich
Acetic acid, glacial, ≥99.99% trace metals basis
Sigma-Aldrich
Sodium hydrogencarbonate, −40-+140 mesh, ≥95%
Sigma-Aldrich
Sodium acetate, ACS reagent, ≥99.0%
Supelco
Hydrocortisone, VETRANAL®, analytical standard
Supelco
Malathion solution, 100 μg/mL in cyclohexane, PESTANAL®, analytical standard
Sigma-Aldrich
2-Ethylhexyl 4-methoxycinnamate, 98%
Sigma-Aldrich
Latanoprost, ≥98% (HPLC)
Supelco
Phylloquinone (K1), analytical standard
Supelco
Cholecalciferol (D3), analytical standard
Supelco
L-Ascorbic acid, analytical standard
Sigma-Aldrich
L-Ascorbic acid, FCC, FG
Supelco
2-Ethylhexyl 4-methoxycinnamate, analytical standard
Supelco
D-Mannitol, ≥99.9999% (metals basis), for boron determination
Sigma-Aldrich
Magnesium, in a Sure/Seal bottle, turnings, anhydrous tetrahydrofuran 37.5 mmol
Supelco
Cyclosporin A, VETRANAL®, analytical standard
Supelco
Sodium bicarbonate concentrate, 0.1 M NaHCO3 in water, eluent concentrate for IC
Supelco
Glycine, analytical standard, for nitrogen determination according to Kjeldahl method
Sigma-Aldrich
(±)-Baclofen, ≥98% (TLC), solid
Sigma-Aldrich
Glycine, BioXtra, ≥99% (titration)
Sigma-Aldrich
2-Fluoroadenine-9-β-D-arabinofuranoside, DNA synthesis and methylation inhibitor
Supelco
(−)-Nicotine solution, 1.0 mg/mL, analytical standard, for drug analysis
Sigma-Aldrich
Riluzole, solid