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Pharmaceutical Research Mar 2017Physiologically-based pharmacokinetic (PBPK) models explicitly incorporate tissue-specific blood flows, partition coefficients, and metabolic processes. Since PBPK... (Review)
Review
Physiologically-based pharmacokinetic (PBPK) models explicitly incorporate tissue-specific blood flows, partition coefficients, and metabolic processes. Since PBPK models are derived using physiologic parameters and interactions of the compound with tissue components, these models are considered to be "bottom up" as opposed to "top down". Modeling approaches can be characterized as either a posteriori (observational) or a priori (based solely on theory). Furthermore, approaches can be mechanistic (structure and components based on mechanisms) or empirical (based on observations alone). Both "bottom up" and "top down" approaches can incorporate either empirical or mechanistic components. In this perspective, we discuss some of the methods and assumptions of current PBPK modeling approaches. Specifically, we discuss drug partitioning into phospholipids and neutral lipids, use of blood-plasma ratios to estimate basic drug tissue partitioning, and clearance of neutral and acidic drugs. Based on these discussions, we believe that current PBPK models are mechanistic but a posteriori and semi-empirical.
Topics: Chemistry, Pharmaceutical; Humans; Models, Biological; Molecular Structure; Pharmaceutical Preparations; Pharmacokinetics; Phospholipids; Tissue Distribution
PubMed: 28028770
DOI: 10.1007/s11095-016-2089-8 -
Nihon Ronen Igakkai Zasshi. Japanese... Jan 1992The elderly are known to be more susceptible to adverse drug reactions. Age differences in pharmacokinetics (i.e., absorption, distribution, metabolism, and elimination)... (Review)
Review
The elderly are known to be more susceptible to adverse drug reactions. Age differences in pharmacokinetics (i.e., absorption, distribution, metabolism, and elimination) may contribute to an increased susceptibility of the elderly to both the therapeutic and toxic effects of some drugs. For many drugs studied, such pharmacokinetic differences are generally consistent with age differences in body composition, renal function, and protein binding. Ageing is associated with a decrease in lean body mass and total body water, and a decline in glomerular and tubular function in the kidney, and diminished cardiac output and liver blood flow. In addition to considering the epidemiology of adverse drug reactions and the altered physiology and pharmacokinetics in the elderly, this review attempts to provide an overview of what is known about the relationship between advanced age and the pharmacokinetics of some drugs mainly eliminated via the kidney. Thus, several methods are presented to permit rational dosage regimen modifications for elderly patients with diminished renal function. Based on a review of the accumulated literature related to clinical geriatric pharmacology, it is concluded that dosage regimen adjustments based on therapeutic drug monitoring are essential to make drug therapy in the elderly safer and more effective.
Topics: Aged; Aging; Drug Monitoring; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Kidney; Liver; Male; Metabolic Clearance Rate; Pharmacokinetics; Tissue Distribution
PubMed: 1560603
DOI: 10.3143/geriatrics.29.10 -
Pharmaceutical Research Sep 2009Drug transporters are recognized as key players in the processes of drug absorption, distribution, metabolism, and elimination. The localization of uptake and efflux... (Review)
Review
Drug transporters are recognized as key players in the processes of drug absorption, distribution, metabolism, and elimination. The localization of uptake and efflux transporters in organs responsible for drug biotransformation and excretion gives transporter proteins a unique gatekeeper function in controlling drug access to metabolizing enzymes and excretory pathways. This review seeks to discuss the influence intestinal and hepatic drug transporters have on pharmacokinetic parameters, including bioavailability, exposure, clearance, volume of distribution, and half-life, for orally dosed drugs. This review also describes in detail the Biopharmaceutics Drug Disposition Classification System (BDDCS) and explains how many of the effects drug transporters exert on oral drug pharmacokinetic parameters can be predicted by this classification scheme.
Topics: Administration, Oral; Animals; Biological Availability; Biotransformation; Carrier Proteins; Half-Life; Humans; Pharmacokinetics
PubMed: 19568696
DOI: 10.1007/s11095-009-9924-0 -
Antimicrobial Agents and Chemotherapy Jul 2021As artemisinin combination therapies (ACTs) are compromised by resistance, we are evaluating triple combination therapies (TACTs) comprising an amino-artemisinin, a...
Toward New Transmission-Blocking Combination Therapies: Pharmacokinetics of 10-Amino-Artemisinins and 11-Aza-Artemisinin and Comparison with Dihydroartemisinin and Artemether.
As artemisinin combination therapies (ACTs) are compromised by resistance, we are evaluating triple combination therapies (TACTs) comprising an amino-artemisinin, a redox drug, and a third drug with a different mode of action. Thus, here we briefly review efficacy data on artemisone, artemiside, other amino-artemisinins, and 11-aza-artemisinin and conduct absorption, distribution, and metabolism and excretion (ADME) profiling and pharmacokinetic (PK) profiling via intravenous (i.v.) and oral (p.o.) administration to mice. The sulfamide derivative has a notably long murine microsomal half-life ( > 150 min), low intrinsic liver clearance and total plasma clearance rates (CL 189.4, CL 32.2 ml/min/kg), and high relative bioavailability ( = 59%). Kinetics are somewhat similar for 11-aza-artemisinin ( > 150 min, CL = 576.9, CL = 75.0 ml/min/kg), although bioavailability is lower ( = 14%). In contrast, artemether is rapidly metabolized to dihydroartemisinin (DHA) ( = 17.4 min) and eliminated (CL = 855.0, CL = 119.7 ml/min/kg) and has low oral bioavailability () of 2%. While artemisone displays low of <10 min and high CL of 302.1, it displays a low CL of 42.3 ml/min/kg and moderate bioavailability () of 32%. Its active metabolite M1 displays a much-improved of >150 min and a reduced CL of 37.4 ml/min/kg. Artemiside has of 12.4 min, CL of 673.9, and CL of 129.7 ml/kg/min, likely a reflection of its surprisingly rapid metabolism to artemisone, reported here for the first time. DHA is not formed from any amino-artemisinin. Overall, the efficacy and PK data strongly support the development of selected amino-artemisinins as components of new TACTs.
Topics: Animals; Antimalarials; Artemether; Artemisinins; Biological Availability; Mice
PubMed: 34097488
DOI: 10.1128/AAC.00990-21 -
Clinical Pharmacokinetics Dec 2022Tucatinib, a highly selective tyrosine kinase inhibitor of the human epidermal growth factor receptor 2 (HER2) approved for HER2-positive metastatic breast cancer, is...
BACKGROUND AND OBJECTIVE
Tucatinib, a highly selective tyrosine kinase inhibitor of the human epidermal growth factor receptor 2 (HER2) approved for HER2-positive metastatic breast cancer, is cleared by hepatic metabolism and subsequent biliary excretion. Liver disease can alter drug disposition and pharmacokinetics (PK). The objective of this study is to characterize PK and safety of tucatinib in volunteers with hepatic impairment.
METHODS
This Phase 1 study compared the PK and safety of a single 300-mg oral dose of tucatinib in volunteers with mild, moderate, and severe hepatic impairment (Child-Pugh A/B/C) to healthy volunteers matched for sex, age, and body mass index. Pharmacokinetic parameters were determined for tucatinib and its predominant metabolite ONT-993.
RESULTS
Compared with healthy volunteers, tucatinib exposure was similar in volunteers with mild impairment and increased in those with moderate or severe impairment without reaching statistical significance. Respective fold increases in geometric mean ratios for AUC and AUC were 1.13 and 1.15 in moderate impairment, and 1.43 and 1.61 in severe impairment compared with healthy volunteers. Three treatment-emergent adverse events (nausea, dermatitis, and increased transaminases) were reported in three volunteers and showed no obvious association with hepatic impairment status.
CONCLUSION
The 1.61-fold geometric mean ratio AUC increase in volunteers with severe hepatic impairment supports the recommendation in the tucatinib prescribing information to reduce the dose from 300 mg twice daily to 200 mg twice daily in patients with severe impairment; no dose adjustment is recommended for patients with mild or moderate hepatic impairment. This trial (NCT03722823) was registered on October 29, 2018.
Topics: Female; Humans; Area Under Curve; Breast Neoplasms; Liver Diseases; Protein Kinase Inhibitors
PubMed: 36471222
DOI: 10.1007/s40262-022-01183-6 -
European Review For Medical and... Dec 2023Amiodarone (AMD), a drug of choice to treat cardiac arrhythmias, has a narrow therapeutic index (NTI). It inhibits CYP3A4, CYP2C9, and CYP2D6 enzymes. Quercetin (QUE), a...
OBJECTIVE
Amiodarone (AMD), a drug of choice to treat cardiac arrhythmias, has a narrow therapeutic index (NTI). It inhibits CYP3A4, CYP2C9, and CYP2D6 enzymes. Quercetin (QUE), a pharmacologically important bioflavonoid in vegetables and fruits, is important in treating cardiovascular comorbidities. QUE alters the bioavailability of drugs used concurrently by dual inhibition of P-glycoproteins (P-gp) and cytochrome (CYP) enzyme systems. The current study aimed to investigate the pre-treatment and co-administration effect of QUE on AMD pharmacokinetics in rats.
MATERIALS AND METHODS
Two separate animal trials (I and II) were planned to probe the effect of QUE on AMD pharmacokinetics by following previously cited studies. The pre-treatment group received oral doses of QUE for 14 days, and a single dose of AMD on the 15th day. Rats were administered single doses of QUE (20 mg/kg) and AMD (50 mg/kg) concurrently in a carboxymethylcellulose (CMC) in the co-administration study. Blood was collected at pre-determined time points. AMD was quantified by HPLC, and data was analyzed by PK solver software.
RESULTS
In the pre-treated group, peak plasma concentration (Cmax) and area under the curve (AUC0-∞) of AMD were increased by 45.52% and 13.70%, respectively, while time to achieve maximum concentration (tmax), half-life (t1/2) and clearance (CL) were declined by 35.72%, 16.75%, and 11.0% respectively compared to the control. In the co-administered group, compared to controls, Cmax and AUC0-∞ were elevated to 12.90% and 7.80%, respectively, while tmax, t1/2, and CL declined by 16.70%, 2.35%, and 13.40%. Further, AMD was increased in lung tissue of both treated groups, relative to the respective controls.
CONCLUSIONS
A notable pharmacokinetic drug interaction between QUE and AMD was observed in rats and warrants possible drug interaction study in humans, suggesting AMD dose adjustment specifically in patients with arrhythmia having a pre-treatment history and simultaneous administration of QUE-containing products.
Topics: Humans; Rats; Animals; Quercetin; Amiodarone; Tissue Distribution; Drug Interactions; Biological Availability; Area Under Curve
PubMed: 38095371
DOI: 10.26355/eurrev_202312_34561 -
Drug Metabolism and Pharmacokinetics Oct 2004Combinatorial chemistry and high-throughput screening have increased the possibility of finding new lead compounds at much shorter time periods than conventional... (Review)
Review
Combinatorial chemistry and high-throughput screening have increased the possibility of finding new lead compounds at much shorter time periods than conventional medicinal chemistry. However, too much promising drug candidates often fail because of unsatisfactory ADME properties. In silico ADME studies are expected to reduce the risk of late-stage attrition of drug development and to optimize screening and testing by looking at only the promising compounds. To this end, many in silico approaches for predicting ADME properties of compounds from their chemical structure have been developed, ranging from data-based approaches such as quantitative structure-activity relationship (QSAR), similarity searches, and 3-dimensional QSAR, to structure-based methods such as ligand-protein docking and pharmacophore modelling. In addition, several methods of integrating ADME properties to predict pharmacokinetics at the organ or body level have been studied. In this article, we briefly summarize in silico ADME approaches.
Topics: Animals; Computer Simulation; Drug-Related Side Effects and Adverse Reactions; Forecasting; Humans; Liver; Models, Biological; Pharmaceutical Preparations; Pharmacokinetics; Structure-Activity Relationship; Tissue Distribution
PubMed: 15548844
DOI: 10.2133/dmpk.19.327 -
Drug Metabolism and Disposition: the... Mar 2016Knowledge of drug absorption, distribution, metabolism, and excretion (ADME) or pharmacokinetics properties is essential for drug development and safe use of medicine.... (Review)
Review
Knowledge of drug absorption, distribution, metabolism, and excretion (ADME) or pharmacokinetics properties is essential for drug development and safe use of medicine. Varied or altered ADME may lead to a loss of efficacy or adverse drug effects. Understanding the causes of variations in drug disposition and response has proven critical for the practice of personalized or precision medicine. The rise of noncoding microRNA (miRNA) pharmacoepigenetics and pharmacoepigenomics has come with accumulating evidence supporting the role of miRNAs in the modulation of ADME gene expression and then drug disposition and response. In this article, we review the advances in miRNA pharmacoepigenetics including the mechanistic actions of miRNAs in the modulation of Phase I and II drug-metabolizing enzymes, efflux and uptake transporters, and xenobiotic receptors or transcription factors after briefly introducing the characteristics of miRNA-mediated posttranscriptional gene regulation. Consequently, miRNAs may have significant influence on drug disposition and response. Therefore, research on miRNA pharmacoepigenetics shall not only improve mechanistic understanding of variations in pharmacotherapy but also provide novel insights into developing more effective therapeutic strategies.
Topics: Animals; Epigenesis, Genetic; Gene Expression Regulation; Humans; Inactivation, Metabolic; MicroRNAs; Pharmaceutical Preparations; RNA Processing, Post-Transcriptional; Transcription Factors
PubMed: 26566807
DOI: 10.1124/dmd.115.067470 -
International Journal of Clinical... Jun 2010
Topics: Area Under Curve; Delayed-Action Preparations; Humans; Nifedipine; Therapeutic Equivalency; Time Factors
PubMed: 20497743
DOI: 10.5414/cpp48355 -
Advanced Drug Delivery Reviews Jan 2013Drug delivery systems involve technology designed to maximize therapeutic efficacy of drugs by controlling their biodistribution profile. In order to optimize a function... (Review)
Review
Drug delivery systems involve technology designed to maximize therapeutic efficacy of drugs by controlling their biodistribution profile. In order to optimize a function of the delivery systems, their biodistribution characteristics should be systematically understood. Pharmacokinetic analysis based on the clearance concepts provides quantitative information of the biodistribution, which can be related to physicochemical properties of the delivery system. Various delivery systems including macromolecular drug conjugates, chemically or genetically modified proteins, and particulate drug carriers have been designed and developed so far. In this article, we review physiological and pharmacokinetic implications of the delivery systems.
Topics: Drug Carriers; Drug Delivery Systems; Pharmaceutical Preparations; Pharmacokinetics; Tissue Distribution
PubMed: 23280371
DOI: 10.1016/j.addr.2012.11.006