Journal: Pharmaceutical research

Article Title: Pharmacokinetics of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Mice: Potential Enterohepatic Circulation and Target-Mediated Disposition

doi: 10.1007/s11095-019-2735-z

Figure Lengend Snippet: Chemical structure of AZD3965.

Article Snippet: For predicting the physicochemical and ADME properties of AZD3965, MedChem Designer Version 4.5.0.12 (Simulations Plus Inc. Lancaster, CA) was used which is based on the software’s built-in algorithm.

Techniques:

Journal: Pharmaceutical research

Article Title: Pharmacokinetics of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Mice: Potential Enterohepatic Circulation and Target-Mediated Disposition

doi: 10.1007/s11095-019-2735-z

Figure Lengend Snippet: The schematic representation of the pharmacokinetic models of AZD3965 following IV and oral administration. Model A describes the EHC by first-order release rate constant from the bile to the absorption site with M-M elimination a. Model B simplifies the EHC process with zero-order release rate from the bile to the systemic circulation b. The key feature of Model C is potential target-mediated drug disposition (TMDD), where AZD3965 binds to its target, MCT1 on the cell surface (kon) to form the drug-transporter complex c. AZD3965 can dissociate from the transporter (koff). The free transporter is subject to turnover, which is characterized a zero-order production rate constant (ksyn) and first-order degradation rate constant (kdeg).

Article Snippet: For predicting the physicochemical and ADME properties of AZD3965, MedChem Designer Version 4.5.0.12 (Simulations Plus Inc. Lancaster, CA) was used which is based on the software’s built-in algorithm.

Techniques:

Journal: Pharmaceutical research

Article Title: Pharmacokinetics of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Mice: Potential Enterohepatic Circulation and Target-Mediated Disposition

doi: 10.1007/s11095-019-2735-z

Figure Lengend Snippet: The plasma concentration profile of AZD3965 after oral a and intravenous b administration. Mice were dosed IV with 10, 50, or 100 mg/kg or orally with 100 mg/kg of AZD3965. Data are expressed as mean ± SD, n = 3–4.

Article Snippet: For predicting the physicochemical and ADME properties of AZD3965, MedChem Designer Version 4.5.0.12 (Simulations Plus Inc. Lancaster, CA) was used which is based on the software’s built-in algorithm.

Techniques: Concentration Assay

Journal: Pharmaceutical research

Article Title: Pharmacokinetics of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Mice: Potential Enterohepatic Circulation and Target-Mediated Disposition

doi: 10.1007/s11095-019-2735-z

Figure Lengend Snippet: Mean pharmacokinetic parameters for AZD3965 after intravenous and oral administration from non-compartmental analysis (NCA). The average weight of female Balb/c mice, 19 g was incorporated for the analysis

Article Snippet: For predicting the physicochemical and ADME properties of AZD3965, MedChem Designer Version 4.5.0.12 (Simulations Plus Inc. Lancaster, CA) was used which is based on the software’s built-in algorithm.

Techniques:

Journal: Pharmaceutical research

Article Title: Pharmacokinetics of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Mice: Potential Enterohepatic Circulation and Target-Mediated Disposition

doi: 10.1007/s11095-019-2735-z

Figure Lengend Snippet: The dose-normalized plasma concentration of AZD3965 in mice after IV administration of doses of 10, 50 or 100 mg/kg a. The effect of increasing AZD3965 dose on the volume of distribution; Vss b, elimination clearance; CL c and terminal slope; λz d where the symbols represent the mean parameter estimate obtained from NCA, Table 1. Data are presented as mean ± SD, n = 3–4.

Article Snippet: For predicting the physicochemical and ADME properties of AZD3965, MedChem Designer Version 4.5.0.12 (Simulations Plus Inc. Lancaster, CA) was used which is based on the software’s built-in algorithm.

Techniques: Concentration Assay

Journal: Pharmaceutical research

Article Title: Pharmacokinetics of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Mice: Potential Enterohepatic Circulation and Target-Mediated Disposition

doi: 10.1007/s11095-019-2735-z

Figure Lengend Snippet: Simultaneous Model A fitting of the plasma AZD3965 concentration-time profile following intravenous (10 a, 50 b, and 100 mg/kg c) and oral (100 mg/kg d) administration. Observed versus predicted plot e and residual plot f. The proposed Model A accounts for potential EHC occurring from the release of bile to the absorption site and back to the systemic circulation with M-M elimination and tlag. Data are presented as mean ± SD, n = 3–4. Symbols depict the observed mean data and the lines represent the model fitted results.

Article Snippet: For predicting the physicochemical and ADME properties of AZD3965, MedChem Designer Version 4.5.0.12 (Simulations Plus Inc. Lancaster, CA) was used which is based on the software’s built-in algorithm.

Techniques: Concentration Assay

Journal: Pharmaceutical research

Article Title: Pharmacokinetics of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Mice: Potential Enterohepatic Circulation and Target-Mediated Disposition

doi: 10.1007/s11095-019-2735-z

Figure Lengend Snippet: Simultaneous Model B fitting of the plasma AZD3965 concentration-time profile following intravenous (10 a, 50 b, and 100 mg/kg c) and oral (100 mg/kg d) administration. Observed versus predicted plot e and residual plot f. The proposed Model B simplifies potential EHC process through the release of bile directly back to the systemic circulation with tlag. Data are presented as mean ± SD, n = 3–4. Symbols depict the observed mean data and the lines represent the model fitted results.

Article Snippet: For predicting the physicochemical and ADME properties of AZD3965, MedChem Designer Version 4.5.0.12 (Simulations Plus Inc. Lancaster, CA) was used which is based on the software’s built-in algorithm.

Techniques: Concentration Assay

Journal: Pharmaceutical research

Article Title: Pharmacokinetics of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Mice: Potential Enterohepatic Circulation and Target-Mediated Disposition

doi: 10.1007/s11095-019-2735-z

Figure Lengend Snippet: Model A, B and C final parameter estimates for AZD3965 obtained from simultaneous model fitting of IV and oral data

Article Snippet: For predicting the physicochemical and ADME properties of AZD3965, MedChem Designer Version 4.5.0.12 (Simulations Plus Inc. Lancaster, CA) was used which is based on the software’s built-in algorithm.

Techniques:

Journal: Pharmaceutical research

Article Title: Pharmacokinetics of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Mice: Potential Enterohepatic Circulation and Target-Mediated Disposition

doi: 10.1007/s11095-019-2735-z

Figure Lengend Snippet: Simultaneous Model C fitting of the plasma AZD3965 concentration-time profile following intravenous (10 a, 50 b, and 100 mg/kg c) and oral (100 mg/kg d) administration. Observed versus predicted plot e and residual plot f. The proposed Model C imparts nonlinearity by potential high-affinity and saturable binding of AZD3965 to its target, MCT1 to form a drug-transporter complex (TMDD behavior). Data are presented as mean ± SD, n = 3–4. and the lines represent the model fitted results.

Article Snippet: For predicting the physicochemical and ADME properties of AZD3965, MedChem Designer Version 4.5.0.12 (Simulations Plus Inc. Lancaster, CA) was used which is based on the software’s built-in algorithm.

Techniques: Concentration Assay, Binding Assay

Journal: Pharmaceutical research

Article Title: Pharmacokinetics of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Mice: Potential Enterohepatic Circulation and Target-Mediated Disposition

doi: 10.1007/s11095-019-2735-z

Figure Lengend Snippet: The physicochemical and absorption, distribution, metabolism and elimination (ADME) properties of AZD3965, predicted from MedChem Designer. The prediction was based on the chemical structure of AZD3965. % represents the chance AZD3965 will be a substrate for the transporter or metabolizing enzyme

Article Snippet: For predicting the physicochemical and ADME properties of AZD3965, MedChem Designer Version 4.5.0.12 (Simulations Plus Inc. Lancaster, CA) was used which is based on the software’s built-in algorithm.

Techniques: