Predicting P-glycoprotein substrates by a quantitative structure–activity relationship model

Gombar, Vijay K.; Polli, Joseph W.; Humphreys, Joan E.; Wring, Stephen A.; Serabjit-Singh, Cosette S.

doi:10.1002/jps.20035

Cited by 110 publications

(93 citation statements)

References 28 publications

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“…To date, there has been no report on whether APZ is a substrate for such drug transporters. However, MDZ, a closely structurally related benzodiazepine, has been shown not to be actively transported by P-glycoprotein or organic anion-transporting polypeptides in vitro (Gombar et al, 2004;Franke et al, 2008). In addition, it is unlikely that intestinal membrane transporters may have any significant impact on the fraction absorbed for APZ under our experimental conditions, because of its high solubility and high permeability.…”

Section: Apz Metabolism In Liver and Smallmentioning

confidence: 81%

Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

Ohtsuka¹,

Yoshikawa²,

Kozakai³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Induction of the cytochrome P450 (P450) enzyme is a major concern in the drug discovery processes. To predict the clinical significance of enzyme induction, it is helpful to investigate pharmacokinetic alterations of a coadministered drug in a suitable animal model. In this study, we focus on the induction of CYP3A, which is involved in the metabolism of approximately 50% of marketed drugs and is inducible in both the liver and intestine. As a marker substrate for CYP3A activity, alprazolam (APZ) was selected and characterized using recombinant CYP3A enzymes expressed in Escherichia coli. Both human CYP3A4 and its cynomolgus P450 ortholog predominantly catalyzed APZ 4-hydroxylation with sigmoidal kinetics. When administered intravenously and orally to cynomolgus monkeys, APZ had moderate clearance; its first-pass extraction ratio after oral dosing was estimated to be 0.09 in the liver and 0.45 in the intestine. Pretreatment with multiple doses of rifampicin (20 mg/kg p.o. for 5 days), a known CYP3A inducer, significantly decreased plasma concentrations of APZ after intravenous and oral administrations (0.5 mg/kg), and first-pass extraction ratios were increased to 0.39 in the liver and 0.63 in the intestine. The results were comparable to those obtained in clinical drug-drug interaction (DDI) reports related to CYP3A induction, although the rate of recovery of CYP3A activity seemed to be slower than rates estimated in clinical studies. In conclusion, pharmacokinetic studies using APZ as a probe in monkeys may provide useful information regarding the prediction of clinical DDIs due to CYP3A induction.

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Section: Apz Metabolism In Liver and Smallmentioning

confidence: 81%

Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

Ohtsuka¹,

Yoshikawa²,

Kozakai³

et al. 2010

Drug Metab Dispos

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“…However, for such agents, unbound plasma concentrations may need to be greater than values projected using receptor affinity data to achieve adequate receptor occupancy for effect. 57 There have been attempts to establish quantitative structure-activity relationship (QSAR) for P-gp, 58 but the task is made difficult by the broad specificity of this transporter.…”

Section: The Blood-brain Barriermentioning

confidence: 99%

Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery

et al. 2005

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Summary:The worldwide market for therapies for CNS disorders is worth more than $50 billion and is set to grow substantially in the years ahead. This is because: 1) the incidence of many CNS disorders (e.g., Alzheimer's disease, stroke, and Parkinson's disease) increase exponentially after age 65 and 2) the number of people in the world over 65 is about to increase sharply because of a marked rise in fertility after World War II. However, CNS research and development are associated with significant challenges: it takes longer to get a CNS drug to market (12-16 years) compared with a non-CNS drug (10 -12 years) and there is a higher attrition rate for CNS drug candidates than for non-CNS drug candidates. This is attributable to a variety of factors, including the complexity of the brain, the liability of CNS drugs to cause CNS side effects, and the requirement of CNS drugs to cross the blood-brain barrier (BBB). This review focuses on BBB penetration, along with pharmacokinetics and drug metabolism, in the process of the discovery and development of safe and effective medicines for CNS disorders.

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“…A total of 261 compounds which were classified as P-gp substrates or nonsubstrates used in this work were cautiously assembled from literature. 10,15,16,20 After removing 12 compounds of overlap data, we constructed SD file format of 261 compounds using PreADMET S/W. 21 The data set consists of 146 substrates and 115 nonsubstrates.…”

Section: Methodsmentioning

confidence: 99%

Prediction Models of P-Glycoprotein Substrates Using Simple 2D and 3D Descriptors by a Recursive Partitioning Approach

Joung

Kim

et al. 2012

Bulletin of the Korean Chemical Society

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P-gp (P-glycoprotein) is a member of the ATP binding cassette (ABC) family of transporters. It transports many kinds of anticancer drugs out of the cell. It plays a major role as a cause of multidrug resistance (MDR). MDR function may be a cause of the failure of chemotherapy in cancer and influence pharmacokinetic properties of many drugs. Hence classification of candidate drugs as substrates or nonsubstrate of the P-gp is important in drug development. Therefore to identify whether a compound is a P-gp substrate or not, in silico method is promising. Recursive Partitioning (RP) method was explored for prediction of P-gp substrate. A set of 261 compounds, including 146 substrates and 115 nonsubstrates of P-gp, was used to training and validation. Using molecular descriptors that we can interpret their own meaning, we have established two models for prediction of P-gp substrates. In the first model, we chose only 6 descriptors which have simple physical meaning. In the training set, the overall predictability of our model is 78.95%. In case of test set, overall predictability is 69.23%. Second model with 2D and 3D descriptors shows a little better predictability (overall predictability of training set is 79.29%, test set is 79.37%), the second model with 2D and 3D descriptors shows better discriminating power than first model with only 2D descriptors. This approach will be used to reduce the number of compounds required to be run in the P-gp efflux assay.

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Predicting P-glycoprotein substrates by a quantitative structure–activity relationship model

Cited by 110 publications

References 28 publications

Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery

Prediction Models of P-Glycoprotein Substrates Using Simple 2D and 3D Descriptors by a Recursive Partitioning Approach

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