DrugBank: a comprehensive resource for in silico drug discovery and exploration

Wishart, David S.

doi:10.1093/nar/gkj067

Cited by 3,315 publications

(2,718 citation statements)

References 9 publications

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“…To consider the influence of CAF on APAP pharmacokinetics,8, 11 an inhibitory effect of CAF on CYP2E1‐mediated NAPQI formation and on ABCB1‐mediated active transport of APAP was mechanistically represented by incorporating competitive inhibition processes in the developed PBPK models 5, 7, 16, 19. Notably, PK simulations following co‐administration of APAP and CAF at toxic dose levels resulted in a decrease of NAPQI concentration in plasma ( Figure 3), which is in accordance with experimental observations obtained in rat liver microsomes 16…”

Section: Resultsmentioning

confidence: 99%

“…When both drugs were given concomitantly, the PICD‐based PD response of APAP (

{P D r e s p o n s e}_{D D I} (|, normalA normalP normalA normalP)

) were adjusted according to its changed concentration‐time profile caused by the competitive inhibition of CAF on ABCB1‐mediated and CYP2E1‐mediated transport and metabolization of APAP, respectively 5, 7, 16, 19. Furthermore, the predicted PD response of CAF (

normalP normalD normalr normale normals normalp normalo normaln normals normale (|, normalC normalA normalF)

) was considered separately.…”

Section: Methodsmentioning

confidence: 99%

“…When APAP is administered at toxic doses, the conjugation of NAPQI with glutathione and the subsequent conversion to APAP cysteine (APAPC) is decreased, which leaves NAPQI as potential binding partner for proteins within the cell 4. Furthermore, APAP and its metabolites are involved in active drug transport processes across extracellular and intracellular membranes mediated by the adenosine triphosphate‐binding cassette (ABC) transporters, in particular ABCB1 and ABCG2 5, 6…”

Section: Figurementioning

confidence: 99%

“…CYP enzymes, particularly CYP1A2 and CYP2E1, are predominantly involved in the metabolism of CAF 7. Moreover, CAF showed inhibitory effects on active drug transport mediated by ABCB1 5. CAF is often administered as combination therapy in the treatment of pain because CAF is supposed to enhance the analgesic effects evoked by APAP or other analgesic agents 8, 9, 10.…”

Section: Figurementioning

confidence: 99%

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Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen‐induced toxicity in humans

Thiel

Cordes

Baier

et al. 2017

CPT Pharmacom & Syst Pharma

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Acetaminophen (APAP) is a widely used analgesic drug that is frequently co‐administered with caffeine (CAF) in the treatment of pain. It is well known that APAP may cause severe liver injury after an acute overdose. However, the understanding of whether and to what extent CAF inhibits or stimulates APAP‐induced hepatotoxicity in humans is still lacking. Here, a multiscale analysis is presented that quantitatively models the pharmacodynamic (PD) response of APAP during co‐medication with CAF. Therefore, drug‐drug interaction (DDI) processes were integrated into physiologically based pharmacokinetic (PBPK) models at the organism level, whereas drug‐specific PD response data were contextualized at the cellular level. The results provide new insights into the inhibitory and stimulatory effects of CAF on APAP‐induced hepatotoxicity for crucially affected key cellular processes and individual genes at the patient level. This study might facilitate the risk assessment of drug combination therapies in humans and thus may improve patient safety in clinical practice.

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Section: Resultsmentioning

confidence: 99%

“…When both drugs were given concomitantly, the PICD‐based PD response of APAP (

{P D r e s p o n s e}_{D D I} (|, normalA normalP normalA normalP)

normalP normalD normalr normale normals normalp normalo normaln normals normale (|, normalC normalA normalF)

) was considered separately.…”

Section: Methodsmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen‐induced toxicity in humans

Thiel

Cordes

Baier

et al. 2017

CPT Pharmacom & Syst Pharma

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“…In the ‘clinical_drug_cancer.txt’ table, each row or entry recorded one pair of patient and drug. After deleting the pairs with missing drug name, we manually standardized the drug names according to NCI drug dictionary and DrugBank (Wishart et al ., 2006). To eliminate the influence of multiple drugs on the survival and simplify the drug response prediction model, we chose the records of those patients who corresponded to one drug, established the list of actual patient–drug pairs, and annotated first‐line, second‐line, or later therapy in each cancer (Table S2).…”

Section: Methodsmentioning

confidence: 99%

Inferences of individual drug responses across diverse cancer types using a novel competing endogenous RNA network

Zhang

Zhou

et al. 2018

Molecular Oncology

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Differences in individual drug responses are an obstacle to progression in cancer treatment, and predicting responses would help to plan treatment. The accumulation of cancer molecular profiling and drug response data provides opportunities and challenges to identify novel molecular signatures and mechanisms of tumor responsiveness to drugs. This study evaluated drug responses with a competing endogenous RNA (ceRNA) system that depended on competition between diverse RNA species. We identified drug response‐related ceRNA (DRCEs) by combining the sequence and expression data of long noncoding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA), and the survival data of cancer patients treated with drugs. We constructed a patient–drug two‐layer integrated network and used a linear weighting method to predict individual drug responses. DRCEs were found to be significantly enriched in known cancer and drug‐associated data resources, involved in biological processes known to mediate drug responses, and correlated to drug activity in cancer cell lines. The dysregulation of DRCE expression influenced drug response‐associated functions and pathways, suggesting DRCEs as potential therapeutic targets affecting drug responses. A further case study in breast invasive carcinoma (BRCA) found that DRCE expression was consistent with the drug response pattern and the aberrant expression of the two NEAT1‐related DRCEs may lead to poor response to tamoxifen therapy for patients with TP53 mutations. In summary, this study provides a framework for ceRNA‐based evaluation of clinical drug responses across multiple cancer types. Understanding the underlying molecular mechanisms of drug responses will allow improved response to chemotherapy and outcomes of cancer treatment.

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Complexity of Medication Regimens for Children With Neurological Impairment

et al. 2021

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IMPORTANCE Parents of children with severe neurological impairment (SNI) manage complex medication regimens (CMRs) at home, and clinicians can help support parents and simplify CMRs.OBJECTIVE To measure the complexity and potentially modifiable aspects of CMRs using the Medication Regimen Complexity Index (MRCI) and to examine the association between MRCI scores and subsequent acute visits. DESIGN, SETTING, AND PARTICIPANTSThis cross-sectional study was conducted between April 1, 2019, and December 31, 2020, at a single-center, large, hospital-based, complex care clinic.Participants were children with SNI aged 1 to 18 years and 5 or more prescribed medications. EXPOSURE Home medication regimen complexity was assessed using MRCI scores. The total MRCI score is composed of 3 subscores (dosage form, dose frequency, and specialized instructions). MAIN OUTCOMES AND MEASURESPatient-level counts of subscore characteristics and additional safety variables (total doses per day, high-alert medications, and potential drug-drug interactions) were analyzed by MRCI score groups (low, medium, and high score tertiles). Associations between MRCI score groups and acute visits were tested using Poisson regression, adjusted for age, complex chronic conditions, and recent health care use. RESULTSOf 123 patients, 73 (59.3%) were male with a median (interquartile range [IQR]) age of 9 (5-13) years. The median (IQR) MRCI scores were 46 (35-61 [range, 8-139]) overall, 29 (24-35) for the low MRCI group, 46 (42-50) for the medium MRCI group, and 69 (61-78) for the high MRCI group.The median (IQR) counts for the subscores were 6 (4-7) dosage forms per patient, 7 (5-9) dose frequencies per patient, and 5 (4-8) instructions per patient, with counts increasing significantly across higher MRCI groups. Similar trends occurred for total daily doses (median [IQR],[31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] doses), high-alert medications (median [IQR], 3 [1-5] medications), and potential drug-drug interactions (median [IQR], 3 [0-6] interactions). Incidence rate ratios of 30-day acute visits were 1.26 times greater (95% CI, 0.57-2.78) in the medium MRCI group vs the low MRCI group and 2.42 times greater (95% CI, 1.10-5.35) in the high MRCI group vs the low MRCI group. CONCLUSIONS AND RELEVANCEHigher MRCI scores were associated with multiple dose frequencies, complicated by different dosage forms and instructions, and associated with subsequent acute visits. These findings suggest that clinical interventions to manage CMRs could target various aspects of these regimens, such as the simplification of dosing schedules.

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DrugBank: a comprehensive resource for in silico drug discovery and exploration

Abstract: DrugBank is a unique bioinformatics/cheminformatics resource that combines detailed drug (i.e. chemical) data with comprehensive drug target (i.e. protein) information. The database contains

Cited by 3,315 publications

References 9 publications

Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen‐induced toxicity in humans

Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen‐induced toxicity in humans

Inferences of individual drug responses across diverse cancer types using a novel competing endogenous RNA network

Complexity of Medication Regimens for Children With Neurological Impairment

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