Assessment of Intestinal Availability (FG) of Substrate Drugs of Cytochrome P450s by Analyzing Changes in Pharmacokinetic Properties Caused by Drug–Drug Interactions

2014 ◽  
Vol 42 (10) ◽  
pp. 1640-1645 ◽  
Author(s):  
Akihiro Hisaka ◽  
Mikiko Nakamura ◽  
Ayako Tsukihashi ◽  
Saori Koh ◽  
Hiroshi Suzuki
Keyword(s):  
Drug Interactions ◽  
Cytochrome P450s ◽  
Pharmacokinetic Properties

Pharmacological profile of antihistamines: focus on unwanted drug interactions

2021 ◽  
Vol 17 (4) ◽  
pp. 46-56
Author(s):  
Alexander S. Dukhanin
Keyword(s):  
Drug Interactions ◽  
Second Generation ◽  
The Body ◽  
Pharmacological Profile ◽  
Luminal Membrane ◽  
Pharmacokinetic Properties ◽  
System 2 ◽  
Specific Affinity ◽  
Histamine H1 Receptors

Differences between individual antihistamines are determined by such pharmacokinetic properties as the rate and completeness of absorption, half-life, the participation of hepatic and renal mechanisms of elimination from the body. Pharmacodynamic features of the antihistamine include selectivity and affinity for histamine H1-receptors and the presence of central effects. The mechanisms of the development of unwanted drug interactions with second-generation antihistamines are analyzed in detail. Three levels of interaction have been identified: 1) hepatic enzymes of the P450 system; 2) membrane carriers of organic anions (OATP) transport proteins on the sinusoidal membrane of hepatocytes and the luminal membrane of the epithelium of the proximal nephron tubule; 3) P-glycoprotein (Pgp, ABCB1-protein) of epithelial cells of the small intestine the area of absorption of oral forms of antihistamines, the epithelium of the proximal tubule and the BBB (blood-brain barrier). The emphasis is made on the description of the dependence of the pharmacological profile of antihistamines on its chemical structure. The elasticity of the bilastine molecule, the ability to induce a change in conformation underlies the high complementarity of bilastine to the recognition site of the H1-receptor which is a high affinity. Experimental evaluation confirms this conclusion: the dissociation constant (Dс) of the bilastin-receptor complex is in the nM concentration range. The bilastine molecule, as a representative of antihistamines with zwitterionic properties, carries both a positive and a negative charge at a physiological pH, making it difficult for its penetration into the brain. The peculiarities of the chemical nature of the bilastine molecule are reflected in the specific pharmacological profile of AGP. In vitro studies have shown a high specific affinity of bilastine for H1-receptors with a very low affinity for other histamine receptors (H2, H3, H4), serotonin, bradykinin, muscarinic and adrenergic receptors). According to this indicator, bilastine is 3 times higher than cetirizine and 5 times higher than fexofenadine. Bilastine is practically not metabolized in the body and is excreted mainly unchanged, and also does not have a cardiotoxic effect. Bilastine is well tolerated; as a therapeutic dose it has a less pronounced sedative potential compared to other second-generation antihistamines.

Pharmacokinetic Properties of New Antiepileptic Drugs

2005 ◽  
Vol 18 (6) ◽  
pp. 444-460 ◽  
Author(s):  
Michele Y. Splinter
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Interactions ◽  
Antiepileptic Drugs ◽  
Drug Monitoring ◽  
The United States ◽  
Therapeutic Drug ◽  
Kinetic Properties ◽  
New Antiepileptic Drugs ◽  
Drug Concentrations ◽  
Pharmacokinetic Properties

Eight new antiepileptic drugs (AEDs) have been approved for use within the United States within the past decade. They are felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide. These afford clinicians with more options to increase efficacy and tolerability in the treatment of patients with epilepsy. Pharmacokinetic properties and drug interactions with other AEDs and other medications taken for comorbidities are individually discussed for each of these new agents. Drug concentrations are not routinely monitored for these newer agents, and there have been few studies designed to investigate their concentration-effect relationships. For most of these medications, the concentrations observed in responders and nonresponders overlap considerably and levels associated with efficacy are often associated with adverse events, complicating the definition of target ranges. Also, epilepsy manifests itself sporadically causing difficulty in clinically monitoring efficacy of medications. Therapeutic drug monitoring provides for the individualization of treatment for these agents, which is important because they demonstrate significant variability in inter- and intraindividual pharmaco-kinetic properties. Therapeutic drug monitoring also allows for identification of noncompliance, drug interactions, and toxicity. Current knowledge of the relationships between efficacy, toxicity, and drug concentrations is discussed.

scholarly journals Identification of Metronidazole – Drug Interactions at the Outpatient Setting in Alkharj

2020 ◽  
pp. 76-80
Author(s):  
Nehad J. Ahmad
Keyword(s):  
Drug Interactions ◽  
Public Hospital ◽  
Low Cost ◽  
Anaerobic Bacteria ◽  
Outpatient Setting ◽  
Qt Interval Prolongation ◽  
Stewardship Program ◽  
Concurrent Use ◽  
Increased Risk ◽  
Pharmacokinetic Properties

Introduction: Metronidazole  is an antibacterial, antiprotozoal and amebicidal agent. It has a good activity against pathogenic anaerobic bacteria, low cost, minor adverse effects and a favorable pharmacodynamic and pharmacokinetic properties but still it interacts with many drugs. Objective: This study aims to assess the interactions of metronidazole with other drugs at the outpatient setting in Alkharj. Methodology: This is a retrospective study include revision of the electronic records in the outpatient setting in a public hospital in Alkharj in order to determine the incidence of interactions between metronidazole and other drugs in 2017. Results: In the present study, the concurrent use of metronidazole with azithromycin, ciprofloxacin, domperidone, formoterol and olanzapine may result in increased risk of QT-interval prolongation and arrhythmias. The use of metronidazole with warfarin may result in increased risk of bleeding. Conclusion: To dispense and prescribe it appropriately antimicrobial stewardship program should be implemented and checking practice should be implemented to avoid the occurrence of Drug - drug interactions.

scholarly journals The Anthelmintic Triclabendazole and Its Metabolites Inhibit the Membrane Transporter ABCG2/BCRP

2012 ◽  
Vol 56 (7) ◽  
pp. 3535-3543 ◽  
Author(s):  
Borja Barrera ◽  
Jon A. Otero ◽  
Estefanía Egido ◽  
Julio G. Prieto ◽  
Anna Seelig ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Anticancer Drugs ◽  
Transepithelial Transport ◽  
Plasma Metabolites ◽  
Milk Secretion ◽  
Active Efflux ◽  
Atp Binding Cassette Transporter ◽  
Drug Pharmacokinetic ◽  
Pharmacokinetic Properties

ABSTRACTABCG2/BCRP is an ATP-binding cassette transporter that extrudes compounds from cells in the intestine, liver, kidney, and other organs, such as the mammary gland, affecting pharmacokinetics and milk secretion of antibiotics, anticancer drugs, and other compounds and mediating drug-drug interactions. In addition, ABCG2 expression in cancer cells may directly cause resistance by active efflux of anticancer drugs. The development of ABCG2 modulators is critical in order to improve drug pharmacokinetic properties, reduce milk secretion of xenotoxins, and/or increase the effective intracellular concentrations of substrates. Our purpose was to determine whether the anthelmintic triclabendazole (TCBZ) and its main plasma metabolites triclabendazole sulfoxide (TCBZSO) and triclabendazole sulfone (TCBZSO2) inhibit ABCG2 activity. ATPase assays using human ABCG2-enriched membranes demonstrated a clear ABCG2 inhibition exerted by these compounds. Mitoxantrone accumulation assays using murine Abcg2- and human ABCG2-transduced MDCK-II cells confirmed that TCBZSO and TCBZSO2are ABCG2 inhibitors, reaching inhibitory potencies between 40 and 55% for a concentration range from 5 to 25 μM. Transepithelial transport assays of ABCG2 substrates in the presence of both TCBZ metabolites at 15 μM showed very efficient inhibition of the Abcg2/ABCG2-mediated transport of the antibacterial agents nitrofurantoin and danofloxacin. TCBZSO administration also inhibited nitrofurantoin Abcg2-mediated secretion into milk by more than 2-fold and increased plasma levels of the sulfonamide sulfasalazine by more than 1.5-fold in mice. These results support the potential role of TCBZSO and TCBZSO2as ABCG2 inhibitors to participate in drug interactions and modulate ABCG2-mediated pharmacokinetic processes.

scholarly journals Drug – Drug Interactions Between Newer Anti- Retroviral Drugs And Anti Epileptics - A Review

2020 ◽  
Vol 11 (3) ◽  
pp. 2963-2967
Author(s):  
Vaishnavi S ◽  
Balaji S ◽  
Ramesh M ◽  
Mothi S N ◽  
Swamy V H T ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Drug Interactions ◽  
Drug Toxicity ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Immunodeficiency Virus ◽  
Pharmacokinetic Properties ◽  
Mechanism Of Interaction ◽  
Cyp 3A

Drug – Drug Interactions (DDIs) are the leading cause of drug toxicity and emergence of drug resistance, ultimately leading to increased burden in People Living with Human Immunodeficiency Virus (PLHIV). On an average 55 % of people on Anti Retroviral Therapy (ARVs) are co-administered with Anti Epileptic Drugs (AEDs). The introduction of newer anti-retroviral drugs such as dolutegravir, bictegravir, emtricitabine, doravirine are proven to have less side effects, high tolerability and effective decrease in the viral load, but the risk of DDIs still stands to be high. This review briefly describes about the pharmacokinetic properties of dolutegravir, bictegravir, emtricitabine, doravirine, mechanism of interaction between the above mentioned ARVs and AEDs, effect of DDIs on ARVs, effect of DDIs on interacting AEDs, outcome of DDIs and possible management of DDIs. The pharmacokinetic type of DDIs was observed between the ARVs and AEDs. The majority of DDIs were found affecting the metabolism and the absorption of the drugs. UGT1A1, CYP 3A are the two important classes of metabolic enzymes involved in the DDIs and p- glycoprotein (P-gp) is the transporter involved in the DDIs affecting the absorption. Significant interactions have been found in between the above mentioned newer ARV’s with carbamazepine, oxcarbazepine, phenytoin and phenobarbitol.

scholarly journals Pharmacokinetic interactions: from mechanisms to clinical relevance

2014 ◽  
Vol 1 (2) ◽  
pp. 85-95
Author(s):  
Amel Ahmane ◽  
◽  
Hocine Gacem ◽  
Karim Boulesbiaat ◽  
Meriem Boullelli
Keyword(s):  
Protein Binding ◽  
Drug Interactions ◽  
Tissue Distribution ◽  
Nuclear Receptors ◽  
Clinical Relevance ◽  
Pharmacokinetic Interaction ◽  
Current Data ◽  
Pharmacological Properties ◽  
Drug Concentrations ◽  
Pharmacokinetic Properties

Among the various types of known drug interactions, those involving pharmacokinetic processes are more complex and dangerous. From digestive pH changes to plasma protein binding and induction or inhibition phenomena; current data used to define, with precision, the sites of interaction. The enzymes involved in metabolism, the transporters involved in tissue distribution and excretion of drugs, and nuclear receptors that regulate the expression of these enzymes and transporters are keys determinants that should be defined for each drug. The clinical relevance of a pharmacokinetic interaction is related to the magnitude of changes in drug concentrations and pharmacological properties of these. Good knowledge of the pharmacokinetic properties of drugs and the mechanisms involved in the genesis of these interactions is, then, needed to prevent and avoid theme.

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