In general, monitor liver function every 1 to 2 months and more frequently when the relationship between abnormal LFTs and hepatotoxicity in patients with such as methotrexate, as cyclosporine itself can cause structural kidney damage. Thiazide diuretics: (Moderate) Coadministration of thiazide diuretics and. Indapamide is a traditional diuretic drug used to treat mild and moderate C selective activator), and indoline methotrexate (an antirheumatic agent). .. ( ) Design, structure-activity relationship, and pharmacokinetic. These synthetic results and the subsequent structure-activity relationship in the preparation of hydrochlorothiazide (12) and some other effective diuretics.
In this process enzyme activity is reduced due to direct interaction with a drug, usually begins with the first dose of the inhibitor, while the extinction of inhibition is related to the drug half-lives. Reversible inhibition Competitive The competitive inhibition occurs when inhibitor and substrate compete for the same binding site on the enzyme. In this type of interaction, the inhibition mechanism is direct and is rapidly reversible. The drugs are converted through multiple CYP dependent steps to nitroso-derivatives that bind with high affinity to the reduced form of CYP enzymes.
Thus CYP enzymes are unavailable for further oxidation and synthesis of new enzymes is therefore, the only means by, which activity can be restored and this may take several days. Some of the inhibitors of CYP3A4 that act by this mechanism of inhibition include azole antifungal agents, some HIV protease inhibitors such as nelfinavir mesylate,[ 39 ] and antihypertensives such as diltiazem. Therefore, propafenone may be induced an increase of venlafaxine plasma concentrations with the development of hallucinations.
Until more data become available, the co-administration of CYP2C19 inhibitors e. Moreover, omeprazole treatment should be well evaluated in elderly patients due the possibility to induce the development of ADR.
In fact, previously we reported in an elderly man the development of delirium probably related to a DDI between omeprazole and amitriptyline through the CYP2C19 inhibition. Due to its long half-life about 30 daysthe risk of interaction must be extended also at the period after the treatment with amiodarone. Moreover, in an open-label study performed in 36 healthy volunteers, the treatment with posaconazole mg twice daily for 14 days increased the plasma concentrations of tacrolimus of 2.
However, in a single-centre study enrolling 20 healthy subjects, Kapil et al. It is consistent with the parenteral administration of a high clearance drug bypassing exposure to gut wall and hepatic CYP3A4 first-pass effects.
Metabolic-intermediate complexes The production of metabolic-intermediate complexes is an unusual form of inibition where the inhibitor binds only to the enzyme-substrate complex. The formation of a metabolic-intermediate complexes results from inhibitors that have an N-alkyl substituent.
Pharmacokinetic drug-drug interaction and their implication in clinical management
After the binding of inhibitor, the latter is oxidized by 3A4 and the resultant oxidized species of the inhibitor remains complexed with the reduced heme group of CYP3A4 forming a complex slowly reversible. Erythromycin is a well-known CYP3A4 inhibitors that use this mechanism of inhibition,[ 60 ] whereas clarythromycin display reduced inhibitory effects with a good clinical efficacy. Once a ligand binds the allosteric site the conformation of the active site changes, its ability to bind the substrate decreases and the product formation tails off.
Many drugs are non-competitive inhibitors of CYP isoforms, as well as omeprazole and lansoprazole, and cimetidine. Irreversible inhibition The metabolite resulting from the oxidation of the substrate by CYP3A4 becomes irreversible and covalently bound to 3A4, thus leading to a permanent inhibition of the enzyme.
In the case of irreversible inhibition the critical factor is represented by the total amount rather than the concentration of the inhibitor to which CYP isoenzyme is exposed. Lipophilic and large molecular size drugs are more likely to cause inhibition.
If the drug is a pro drug the effect is decreased. The co-administration of 3A4 inhibitors with the hydroxymethylglutaryl-coenzyme A reductase inhibitors statins; e.
Exposure to environmental pollutants as well as the large number of lipophilic drugs can result in induction of CYP enzymes. The most common mechanism is transcriptional activation leading to increased synthesis of more CYP enzyme proteins. Rifampicin increases the elimination of a large number of drugs, although most of them are substrates for CYP3A4, such as midazolam, quinidine, cyclosporine A and many steroids.
Metabolism of the affected drug is increased leading to decreased intensity and duration of drug effects. A complicating factor is that the time-course of induction depends on the time required for enzyme degradation and new enzyme production.
These enzyme-induction reactions also occur with smoking and long-term alcohol or drug consumption and can reduce the duration of action of a drug by increasing its metabolic elimination.
Recently, we documented in a patient with epilepsy a DDI between phenobarbital and lamotrigine that induced the development of leukopenia and thrombocytopenia. We postulated that CYP enzyme induction by phenobarbital could be responsible for the production of reactive metabolites of lamotrigine that might be causative for the observed hematologic effects.
The excretion through saliva, sweat and lungs for volatile drugs and milk has little quantitative significance, but the milk is important when the drugs can reach the baby during lactation. Drugs are excreted mainly through: Renal tubular excretion glomerular filtration, tubular reabsorption and active tubular secretion Biliary excretion. The interaction may occur for a mechanism of competition at the level of active tubular secretion, where two or more drugs use the same transport system.
An example is given by NSAIDs that determine the appearance of toxic effects caused by methotrexate when the renal excretion of the anti-proliferative drug is blocked. For example, probenecid can increase the serum concentration of penicillins and cephalosporins, delaying their renal excretion and thus saving in terms of dosage.
In fact, probenecid acts by competitively inhibiting an organic anion transporter in renal tubules, thus increasing plasma concentrations of other transporter substrates, while reducing their excretion.
In particular, cimetidine, an H2 receptor inhibitor, may influence the tubular secretion of different molecules.
The interactions can also occur during tubular reabsorption. Many drugs, when they are in an ionized form in the urine, pass by diffusion in tubular cells. The changes in urinary pH, pharmacologically induced, influence the state of ionization of certain drugs and may therefore affect the re-absorption from the renal tubule.
The changes in urinary pH, however, assume practical importance only if the pKa of the drug, i. In fact, the pKa values can cause appreciable changes in the degree of dissociation of the drug.
Compounds such as ammonium chloride, tromethamine and diuretics, being able to change urine pH, may affect the excretion of several acidic and basic drugs,[ 15 ] and this interaction may be used to facilitate the removal of drugs from the body.
On the contrary, the interaction between diuretics and lithium salts can still have negative effects on the patient.SAR of phenylethanolamine /SAR of sympathomimetics
Lithium is a monovalent cation whose excretion is influenced by changes of serum sodium. Therefore, a high excretion of sodium induced by chronic treatment with some diuretics such as thiazides, may increase lithium re-absorption, causing serious toxic effects from relative over dosage.
The speed transfer of molecules depends on the availability of the transporter, a protein that allows the transfer through the cellular membranes. Therefore, when two drugs are substrate of the same transmembrane transporter they can complete each other, up to the saturation of transporter capacity. At that time, the rate of elimination approaches to a zero order saturable process.
Unfortunately, DDI cannot be listed exhaustively. In fact, in an Italian study cross-sectional study, was found that the 3. Moreover, even if not always available and feasible, the adoption of therapeutic drug monitoring protocols in the above reported patients i.
Therefore, we hope that the National Health System plan a strategy intervention to keep physicians adequately aware of potential DDI, with particular regard to widely used medications.
However, in this time, reports on DDIs that consider different sources updated on the basis of current evidence from the literature should be useful to evaluate a possible risk of DDI particularly in elderly patients with poly-therapy. Previously it has been reported that genetic polymorphism of CYP enzymes played a significant role in the clinical effects of drug treatment[ 79596 ] as well as in the development of DDIs.
However, may be underlined that only two drugs are able to induce the development of a DDI even if this clinical relevance is related to the pharmacology of each drug.
In fact, a DDI will be able to induce a clinically relevant effect in presence of drugs with a low therapeutic index, a long half-life and a higher bound with plasma proteins. Moreover, it is important to underline that the development of DDI is not a problem a class of drug but of a single drug and this problem could be under estimated considering the SPC only. Footnotes Source of Support: Adverse drug reaction monitoring: Doing it the French way. The incidence of antimicrobial allergies in hospitalized patients: Implications regarding prescribing patterns and emerging bacterial resistance.
Analysis of the direct cost of adverse drug reactions in hospitalised patients. Eur J Clin Pharmacol. Adverse drug reactions to antibiotics observed in two pulmonology divisions of catanzaro, Italy: A six-year retrospective study. Retrospective analysis of adverse drug reactions to bronchodilators observed in two pulmonary divisions of Catanzaro, Italy.
Retrospective evaluation of adverse drug reactions induced by nonsteroidal anti-inflammatory drugs. Prospective randomized double-blind trial of racecadotril compared with loperamide in elderly people with gastroenteritis living in nursing homes. Drug therapeutic failures in emergency department patients.
A university hospital experience. Johnell K, Klarin I. The relationship between number of drugs and potential drug-drug interactions in the elderly: A study of overelderly patients from the Swedish Prescribed Drug Register.
- PDR Search
Irinotecan synergistically enhances the antiproliferative and proapoptotic effects of axitinib in vitro and improves its anticancer activity in vivo. Optimising drug treatment for elderly people: Mantia G, Provenzano G. Rilevanza clinica delle interazioni farmacologiche di tipo farmacocinetico. Pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers. Ogawa R, Echizen H. Drug-drug interaction profiles of proton pump inhibitors.
Clinical use of tetracyclines in the treatment of periodontal diseases. Clinically significant drug interactions with antacids: Seedher N, Agarwal P. Effect of metal ions on some pharmacologically relevant interactions involving fluoroquinolone antibiotics.
Drug Metabol Drug Interact. Use and indications of cholestyramine and bile acid sequestrants.
Effects of colestipol hydrochloride on drug absorption in the rat II. Effect of prokinetic agents, cisapride and metoclopramide, on the bioavailability in humans and intestinal permeability in rats of ranitidine, and intestinal charcoal transit in rats. Res Commun Mol Pathol Pharmacol.
Effect of metoclopramide on digoxin absorption from tablets and capsules. Regulation and function of the multidrug resistance genes in liver. In vitro and in vivo drug interactions involving human CYP3A.
For example, ALT and AST are present in other tissues heart, brain and skeletal muscle besides the liver and so they are released into the circulation when there is damage to these tissues. AST mostly increases in case of myocyte damage due to extreme physical effort Ozer et al.
LDH is another enzyme occasionally used as a biomarker of hepatocellular injury. However, it is not routinely employed since its specificity is questionable Ramaiah, More recently genomics, proteomics and metabolomics have been proposed as valuable techniques for discovering biomarkers Amacher et al.
However, the most of the datasets is not suitable to be used alone for classification modeling. In conclusion, the data we used for modeling have a certain level of uncertainty due to these points which may have influenced the reliability and performance of the model.
An alternative that could limit the uncertainty linked to hepatotoxicity data is to use in vitro data obtained if possible on the same cell lines and using the same laboratory assay and conditions. However, not much public data is available in the open literature for this purpose and this approach too suffers some limitations such as the influence of genetic and environmental factors in the variations of biochemistry Przybylak and Cronin, Mechanistic Explanation of SAs We propose, when possible, a mechanistic rationale using the information in the literature and in public databases PubChem https: N-Containing Heterocyclic Aromatic Compounds: Pyridine, Pyrazine, Pyrimidine This SA, identified by the ID number 1 Table 1is a generic chemical structure that may be seen in several different chemical families.
In the training set it matches 57 compounds covering different chemical and therapeutic classes41 of them classified as hepatotoxic.
Considering the lack of specificity of this SA, it is impossible to highlight any single mechanism of action that may explain the toxicity. In the training set this chemical fragment correctly identified hepatotoxic compounds in However, we identified two sub-families in this large group of drugs.
The first comprises a group of three drugs used for the treatment of malaria amodiaquin, primaquine, mefloquine. The hepatotoxicity of these molecules are mainly linked to hypersensitivity reactions LiverTox database, http: The second includes seven chemical compounds used in the therapy of several cancer types methotrexate, amsacrine, bortezomib, imatinib mesilate, intoplicine, OSI, rubitecan.
Methotrexate is a methyl analog of folic acid, used in the treatment of various neoplastic diseases. A reasonable part of the population treated with this drug reported liver injury.
Pharmacokinetic drug-drug interaction and their implication in clinical management
Thin fibrous septa extending from the portal tracts into the lobules, often in a stellate configuration is the typical pattern of liver fibrosis induced by methotrexate. Persistent fibrosis eventually may lead to cirrhosis Hytiroglou et al. The mechanisms of liver injury of bortezomib are still unclear. It is metabolized in the liver largely through the CYP 3A4 pathway and liver injury may be related to production of a toxic intermediate LiverTox database.
Therapy with imatinib may lead to three forms of acute liver injury: Metabolism of OSI occurs in liver and preclinical repeated dose toxicity studies reported liver injury at higher doses. In a recent study O'Bryant et al.
Sulphonamides This SA identified by the ID number 2 Table 1 matches chemicals containing a sulfonamide group in their structures. Most of the compounds correctly predicted as hepatotoxic by this SA are sulfonamide antibiotics. Several compounds belonging to this class have been reported to cause mild cholestasis hepatitis, but severe and even fatal cases have occurred Polson, From a histopathological point of view centrilobular cholestasis is frequent in sulfonamide hepatotoxicity with only mild to moderate mixed portal inflammation of lymphocytes, and small numbers of eosinophils and neutrophils Murray et al.
Granulomatous hepatitis is uncommon but it can occur with many of the sulfonamides while massive hepatocellular necrosis has been described in fatal cases Murray et al. This SA matched 12 compounds in the training set, eight of them are labeled as hepatotoxic.
However, more severe liver diseases, such as hepatitis and or intrahepatic cholestasis, have been reported: Amoxicillin which is normally used in combination with clavulanic acid in order to reduce antibiotic-resistance can cause from mild to moderate hepatitis that rarely leads to liver failure.
The mechanism of action that leads to toxicity is still not completely clear. However, several human leukocyte antigen haplotypes have been found to be related with hepatotoxicity, especially in the elderly Pugh et al. A few severe reactions, including bile duct damage have been reported Cundiff and Joe, Prolonged treatment with flucloxacillin in the elderly has been associated with jaundice Fairley et al. Four compounds are found in the first class: Some cases of liver injury have been reported in patients taking zidovudine, but stavudine is responsible for more severe hepatotoxicity Nunez,