Pharmacokinetics Of Co-administered Drugs Research Articles

Improving antibacterial prescribing safety in the management of COPD exacerbations: systematic review of observational and clinical studies on potential drug interactions associated with frequently prescribed antibacterials among COPD patients.

BackgroundGuidelines advise the use of antibacterials (ABs) in the management of COPD exacerbations. COPD patients often have multiple comorbidities, such as diabetes mellitus and cardiac diseases, leading to polypharmacy. Consequently, drug–drug interactions (DDIs) may frequently occur, and may cause serious adverse events and treatment failure.Objectives(i) To review DDIs related to frequently prescribed ABs among COPD patients from observational and clinical studies. (ii) To improve AB prescribing safety in clinical practice by structuring DDIs according to comorbidities of COPD.MethodsWe conducted a systematic review by searching PubMed and Embase up to 8 February 2018 for clinical trials, cohort and case–control studies reporting DDIs of ABs used for COPD. Study design, subjects, sample size, pharmacological mechanism of DDI and effect of interaction were extracted. We evaluated levels of DDIs and quality of evidence according to established criteria and structured the data by possible comorbidities.ResultsIn all, 318 articles were eligible for review, describing a wide range of drugs used for comorbidities and their potential DDIs with ABs. DDIs between ABs and co-administered drugs could be subdivided into: (i) co-administered drugs altering the pharmacokinetics of ABs; and (ii) ABs interfering with the pharmacokinetics of co-administered drugs. The DDIs could lead to therapeutic failures or toxicities.ConclusionsDDIs related to ABs with clinical significance may involve a wide range of indicated drugs to treat comorbidities in COPD. The evidence presented can support (computer-supported) decision-making by health practitioners when prescribing ABs during COPD exacerbations in the case of co-medication.

The alteration of pharmacokinetics of erlotinib and OSI420 in type 1 diabetic rabbits.

Alterations in blood glucose levels observed in diabetes, may change the pharmacokinetics of co-administered drugs and in consequence, the efficacy and safety of therapy. Many oncological patients are diabetics and it is important to determine the interaction of anticancer drugs with this chronic disease. Erlotinib is a tyrosine kinase inhibitor (TKI), approved for the treatment of patients with non-small-cell lung cancer and pancreatic cancer in combination with gemcitabine. The aim of the study was to investigate the influence of the diabetes on the pharmacokinetics of erlotinib in rabbits. Additionally, the effect of erlotinib on glucose levels was examined. The pharmacokinetics of erlotinib was studied in healthy rabbits (n=6, control group) and type 1 diabetic rabbits (n=6, diabetic group). Erlotinib was administered in a single oral dose of 25mg. Plasma concentrations of erlotinib and its metabolite (OSI420) were measured with the validated method. The plasma concentrations of erlotinib and OSI420 were markedly increased in diabetic rabbits. Statistically significant differences between the groups were revealed for almost all analysed pharmacokinetic parameters for erlotinib and OSI420. The maximum glycaemia drop of 7.7-33.5% was observed in the diabetic animals, but no significant changes in glucose concentration were observed in the control group. The research proved the significant influence of diabetes on the pharmacokinetics of erlotinib and OSI420. Due to higher exposure to erlotinib, there may be an increased risk of adverse drug reactions in diabetic patients. Therefore, in some cases lower doses of the drug should be considered.

Inhibition of Human Cytochrome P450 Enzymes 3A4 and 2D6 by β‐Carboline Alkaloids, Harmine Derivatives

β-Carboline alkaloids are the main chemical constituents of the plant Peganum harmala, while they also could be formed endogenously and found in coffee, alcoholic beverages and tobacco. Considering the fact that the possibility of herb-drug interactions has recently received great attention worldwide, the aim of the current study was to assess the potential for the metabolism-based drug-drug interactions arising from five β-carboline alkaloids (harmine, harmaline, harmalol, harmol and harmane) from P. harmala in vitro. With microsome incubation assays and UPLC/HPLC methods, the inhibitions on human liver CYP3A4 and CYP2D6 enzymes by those β-carboline alkaloids were studied kinetically. Harmine, harmol and harmane exhibited noncompetitive inhibition on the activity of CYP3A4 with K(i) values of 16.76, 5.13 and 1.66 μM, respectively. These β-carboline alkaloids were also found to be both substrates and inhibitors for CYP2D6. Harmaline, harmine and harmol showed typical competitive inhibition on the activity of CYP2D6 with K(i) values of 20.69, 36.48 and 47.11 μM, respectively. The inhibition of the two major CYP enzymes by those β-carboline alkaloids suggested that changes in the pharmacokinetics of co-administered drugs were likely to have occurred. Therefore, caution should be exercised for possible drug interactions of medicinal plants containing those β-carboline alkaloids and CYP substrates.

Inhibition of cytochrome P450 enzymes by rhein in rat liver microsomes

Rhein, an active ingredient extensively found in plants such as Aloe, Cassitora L., rhubarb and so on, has been used for a long time in China. Pharmacological tests revealed that rhein not only had a strong antibacterial action, but also may be useful in cancer chemotherapy as a biochemical modulator. Its therapeutic action and toxicity is still the subject of considerable research. With microsome incubation assays in vitro and HPLC methods, the inhibition of rat liver CYP1A2, CYP2C9, CYP2D6, CYP2E1 and CYP3A enzymes by rhein were studied kinetically. The results showed the most inhibition of CYP2E1 by rhein (K(i) = 10 microm, mixed); CYP3A and CYP2C9 were also inhibited by rhein, K(i) = 30 microm (mixed) and K(i) = 38 microm (mixed), respectively; rhein revealed some inhibition of CYP1A2 (K(i) = 62 microm, uncompetitive) and CYP2D6 (K(i) = 74 microm, mixed). Drug-drug interactions, especially cytochrome P450 (CYP)-mediated interactions, cause an enhancement or attenuation in the efficacy of co-administered drugs. Inhibition of the five major CYP enzymes observed for rhein suggested that changes in pharmacokinetics of co-administered drugs were likely to occur. Therefore, caution should be paid to the possible drug interaction of medicinal plants containing rhein and CYP substrates.

Cytochrome P450 Inactivation by Pharmaceuticals and Phytochemicals: Therapeutic Relevance

One of the major clinical concerns is possible drug interactions that can be the result of abrogation of the P450 pathway(s) of metabolism causing toxicity due to elevated exposures of other drugs metabolized by these pathways. When the P450 substrate is catalytically activated to a reactive intermediate, this transient molecule may react with available nucleophilic residues from the enzyme – thereby resulting in the inactivation of the P450. The effects of CYP inactivation on the pharmacokinetics of co-administered drugs or on the inactivator itself depend on complex factors involving the molecular entities, the kinetics of inactivation (KI, kinact), the partition ratio, the zero-order synthesis rate of new enzyme, multiple pathways of metabolism (competing pathways), the dose or exposure, and specific patient characteristics. This review summarizes the catalytic efficiencies of many inactivator drugs along with any consequent clinical relevance. The chemical agents described have been ranked for the kinetic efficiency of inactivation and contrasted with the known clinically relevant drug interactions. This will allow judicious consideration of the many factors that influence the importance of CYP inactivation and their relative contribution to systemic clearance of co-administered drugs. This study allows an improved characterization and dissection of potential physiological interactions with various drugs and nutrients. Knowing more about selective inactivation of cytochrome P450 by common xenobiotics, drugs and phytochemicals allows better understanding of expected interactions with chemotherapeutics and other xenobiotics.