To address pharmacokinetic and toxicological issues in drug development, once the main source of late attrition of drug candidates, many pharmaceutical companies have now implemented early DMPK (Drug Metabolism and Pharmacokinetics) or early toxicological studies. However, such approaches are difficult to emulate in the academic drug discovery environment. Therefore, we began an initiative “Development of a Drug Discovery Informatics System” in collaboration with several other research groups. The main aim of this initiative is to develop more accurate prediction systems for DMPK and toxicological properties primarily targeting academic scientists. Our group’s focus is to develop a pharmacokinetics database and prediction models.
Any good prediction system depends on high-volume, high-quality training datasets. We collected pharmacokinetic and physicochemical parameters from the public bioactivity database, ChEMBL. However, since ChEMBL compiles data obtained in different experimental conditions, we developed a curation workflow to select the data measured in compatible conditions and to reformat the results as appropriate for our prediction system.
In addition to the public data, we have acquired both in vitro and in vivo experimental data under unified protocols. The in vitro experiments include physicochemical parameters such as solubility and distribution coefficient, and pharmacokinetic parameters such as metabolic stability, protein binding in plasma, protein binding in brain homogenate, and blood-to-plasma concentration ratio. In addition, we collected efflux ratio of P-glycoprotein (P-gp), which is the major transporter in gut and brain. The in vivo data include the drug concentrations in plasma and tissues after oral or intravenous administration of the drug and pharmacokinetic parameters calculated therefrom.
We are currently developing several prediction models using these data, and we intend to provide them sequentially. Any questions or comments are welcomed to drumap[at]nibiohn.go.jp (please replace [at] with @).
Current version contains following chemicals and activity data.
Number of records | |
---|---|
All registered compounds | 30,633 |
Freebase compounds | 27,239 |
Freebase compounds ignoring stereo structure | 25,387 |
Physicochemical parameters | |||||
---|---|---|---|---|---|
Parameter name | Parameter type | Species | Our experimental data | Curated public data | predicted data |
Solubility (pH 7.4) | Sol7.4 | None | 163 | 367 | 27,239 |
Solubility (pH 1.2) | Sol1.2 | None | 163 | ||
Distribution coefficient (pH 7.4) | logD7.4 | None | 120 |
In vitro parameters | |||||
---|---|---|---|---|---|
Parameter name | Parameter type | Species | Our experimental data | Curated public data | predicted data |
Fraction unbound in plasma | Fu,p | Human | 441 | 2,319 | 27,239 x 2 |
Rat | 422 | 27,239 x 2 | |||
Fraction unbound in brain homogenate | Fu,brain | Rat | 443 | ||
Mammal | 253 | 27,239 | |||
Blood-to-plasma concentration ratio | Rb | Human | 213 | ||
Hepatic intrinsic clearance in liver microsome | CLint | Human | 166 | 5,275 | 27,239 |
Rat | 167 | ||||
Probability metabolized by each cytochrome P-450 (1A2, 2C9, 2D6, 3A4) | CYP | Human | 27,239 x 4 | ||
Site metabolized by each cytochrome P-450 (1A2, 3A4) | CYP | Human | 2,673 + 2,814 | ||
Apical-to-basolateral apparent permeability coefficient (Caco-2) | Papp | Human | 4,408 | 27,239 | |
Apical-to-basolateral apparent permeability coefficient (LLC-PK1) | Papp | Human | 462 | 27,239 | |
P-gp net efflux ratio (LLC-PK1) | NER | Human | 446 | 27,239 |
In vivo parameters | |||||
---|---|---|---|---|---|
Parameter name | Parameter type | Species | Our experimental data | Curated public data | predicted data |
Drug concentration in 7 tissues*1 or plasma | C | Rat | 100 | ||
Initial drug concentration in plasma | C0 | Rat | 39 | ||
Peak drug concentration in 7 tissues*1 or plasma | Cmax | Rat | 96 | ||
Elimination half-life of a drug in 7 tissues*1 or plasma | T1/2 | Rat | 100 | ||
Time to reach peak drug concentration in 7 tissues*1 or plasma | Tmax | Rat | 96 | ||
Area under the drug concentration-time curve in 7 tissues*1 or plasma | AUC | Rat | 100 | ||
Mean residence time of a drug in plasma | MRT | Rat | 100 | ||
Volume of distribution | Vd | Rat | 39 | ||
Apparent volume of distribution at oral administration | Vd/F | Rat | 96 | ||
Clearance | CL | Rat | 39 | ||
Apparent clearance at oral administration | CL/F | Rat | 96 | ||
Renal clearance | CLr | Human | 401 | 27,239 | |
Bioavailability | F | Rat | 35 | ||
Fraction absorbed | Fa | Human | 945 | 27,239 | |
Fraction excreted in urine | Fe | Human | 343 | 27,239 | |
Excretion type in urine | CR type | Human | 27,239 |
Toxicity data | |||||
---|---|---|---|---|---|
Parameter name | Parameter type | Species | Data provided by accompanying projects | ||
IC50 for hERG channel | IC50 | Human | 9,114 | ||
IC50 for Cav1.2 channel | IC50 | Human | 204 | ||
IC50 for Kv1.5 channel | IC50 | Human | 686 | ||
IC50 for Nav1.5 channel | IC50 | Human | 1,321 | ||
Link to Hepatotoxicity database | Human and rat | 620 |
This research was supported by the Drug Discovery Support Promotion Project from Japan Agency for Medical Research and Development, AMED.