Edith Albengres

Systemic Antifungal Agents: Drug Interactions of Clinical Significance

SummaryThere are 3 main classes of systemic antifungals: the polyene macrolides (e.g. amphotericin B), the azoles (e.g. the imidazoles ketoconazole and miconazole and the triazoles itraconazole and fluconazole) and the allylamines (e.g. terbinafine). Other systemic antifungals include griseofulvin and flucytosine.Most drug-drug interactions involving systemic antifungals have negative consequences. The interactions of amphotericin B, flucytosine, griseofulvin, terbinafine and azole antifungals can be divided into the following categories: (i) additive dangerous interactions; (ii) modifications of antifungal kinetics by other drugs; and (iii) modifications of the kinetics of other drugs by antifungals.Amphotericin B and flucytosine mainly interact with other agents pharmacodynamically. Clinically important drug interactions with amphotericin B cause nephrotoxicity, hypokalaemia and blood dyscrasias. The most important drug interaction of flucytosine occurs with myelotoxic agents.Hypokalaemia can precipitate the long QT syndrome, as well as potentially lethal ventricular arrhythmias like torsade de pointes. Synergism is likely to occur when either QT interval-modifying drugs (e.g. terfenadine and astemizole) and drugs that induce hypokalaemia (e.g. amphotericin B) are coadministered.Induction and inhibition of cytochrome P450 enzymes at hepatic and extrahepatic sites are the mechanisms that underlie the most serious pharmacokinetic drug interactions of the azole antifungals. These agents have been shown to notably decrease the catabolism of numerous drugs: histamine H1 receptor antagonists, warfarin, cyclosporin, tacrolimus, digoxin, felodipine, lovastatin, midazolam, triazolam, methylprednisolone, glibenclamide (glyburide), phenytoin, rifabutin, ritonavir, saquinavir, nevirapine and nortriptyline. Non-antifungal drugs like carbamazepine, phenobarbital (phenobarbitone), phenytoin and rifampicin (rifampin) can induce the metabolism of azole antifungals. The bioavailability of ketoconazole and itraconazole is also reduced by drugs that increase gastric pH, such as H2 receptor antagonists, proton pump inhibitors, sucralfate and didanosine.Griseofulvin is an enzymatic inducer of coumarin-like drugs and estrogens, whereas terbinafine seems to have a low potential for drug interactions.Despite important advances in our understanding of the mechanisms underlying pharmacokinetic drug interactions during the 1990s, at this time they still remain difficult to predict in terms of magnitude in individual patients. This is because of the large interindividual and intraindividual variations in the catalytic activity of those metabolising enzymes that can either be induced or inhibited by various drugs. Notwithstanding these variations, increasing clinical experience is allowing pharmacokinetic interactions to be used to advantage in order to improve the tolerability of some drugs, as recently exemplified by the use of a fixed combination of ketoconazole and cyclosporin.

Drug binding in plasma. A summary of recent trends in the study of drug and hormone binding.

SummaryThe ligands are generally bound in plasma to a significant extent by several transport proteins (both high and low affinity), irrespective of their endogenous or exogenous origin. The protein binding of endogenous compounds (such as hormones) exhibits higher affinity and specificity than those of exogenous compounds (such as drugs). For plasma proteins that bind the same ligand(s), structural similarities or a common genetic origin may be found, although this is not a general rule. Alterations in ligand binding may be due to modifications of either the structure or the level of the binding protein. These modifications may result from genetic make up, physiology or pathology. In some situations, plasma binding may impair the distribution of drugs to tissues, with drug distribution then mainly restricted to the distribution compartment of the drug-binding protein. In other instances, the plasma drug-binding is permissive, and does not limit drug distribution to tissues. A given drug-transport protein system may have either a permissive or a restrictive effect on the drug distribution, depending on the tissue.The physiological significance of the high-affinity transport proteins is not completely understood. These proteins may increase the plasma concentration of poorly hydrosoluble ligands, ensure a more uniform tissue distribution and increase the life of the ligands. The life of the protein may also be increased by ligand binding. High-affinity transport proteins are also involved in some specific carrier mediated transfer mechanisms. It is possible to demonstrate structure-binding relationships or binding selectivity for the plasma transport proteins, but these are quite independent of relationships observed at the receptor level.

Evidence for binding of certain acidic drugs to α1-acid glycoprotein

The binding of some acidic drugs to alpha 1-AGP was studied by equilibrium dialysis at 37 degrees, pH 7.4. Certain acidic drugs bound to alpha 1-AGP at one binding site with a high affinity. Though the alpha 1-AGP plasma concentration is far lower than the HSA concentration, the association constants of some acidic drugs with alpha 1-AGP are high enough to suggest that binding to alpha 1-AGP will contribute significantly to the total plasma binding of these drugs.

Plasma Protein Binding and Erythrocyte Partitioning of Nicardipine In Vitro

Summary: Using isotope techniques, equilibrium dialysis, and incubation experiments, we characterized the binding of nicardipine to isolated plasma proteins, human serum, blood cells, and platelets. Nicardipine was mainly bound to lipoproteins, orosomucoïd, albumin, and erythrocytes in human blood. Nicardipine, pindolol, and imipramine were found to share the same site on orosomucoïd. The determinants of nicardipine binding to lipoproteins were triglycerides, phospholipids, and cholesterol ester. Nicardipine partitioned into erythrocytes, showing a constant ratio of distribution between the intra- and extracellular compartments. Nicardipine partitioned less to erythrocytes when increasing amounts of binding plasma proteins were present in the extracellular compartment. In human blood, 12 to 18% of total nicardipine was present in erythrocytes. The overall binding of nicardipine in serum varied from 98 to 99.5% and correlated with serum orosomucoïd and serum lipid concentrations.

A Case of Destructive Polyarthropathy in a 17-Year-Old Youth Following Pefloxacin Treatment

SummaryJoint and muscle pain have been reported with quinolones; however, arthropathies induced by quinolones do not result in erosive changes in humans, although such changes have occurred in animal studies.We report an unusual case of destructive polyarthropathy in a 17-year-old boy after treatment with pefloxacin 800 mg/day for 3 months. Pefloxacin may have accentuated the cartilage damage in this case, even if an underlying joint disease could not be excluded.

Blood binding and tissue uptake of drugs. Recent advances and perspectives

Summary— The free drug hypothesis, which states that only the unbound moiety of drug in blood is available for tissue diffusion, is discussed according to recent investigations. In some experimental conditions, it must be assumed that part of the protein‐bound drug in plasma is extracted during a single passage through the organ studied. The mechanisms underlying these observations are not unequivocal and remain hypothetical. In the liver, high‐affinity binding sites for serum albumin have been demonstrated, and they would explain the high extraction by liver of endogenous and exogenous compounds.

Role of alpha-1 acid glycoprotein, albumin, and nonesterified fatty acids in serum binding of apazone and warfarin.

Altered concentrations of serum proteins and nonesterified fatty acids (NEFAs) often accompany malignant diseases. Free fractions (fu) of apazone and warfarin were measured by equilibrium dialysis in serum samples obtained from 31 patients with cancer and 18 control subjects. Mean fuvalues of both drugs were significantly higher in the patient group. Multivariate analysis showed albumin, NEFA, and AAG for apazone and albumin, NEFA, and age for warfarin accounted for 60% and 63%, respectively, of interpatient variation in bound/free drug concentration ratios in the group of patients with cancer. The interactions of apazone and warfarin with AAG were further characterized; the more avid site had association constants of 4.5 × 105and 2.3 × 105 L/mol, respectively. Finally, it is strongly suggested that when hypoalbuminemia is present and a drug binds to AAG with an affinity constant comparable to or higher than that to albumin, then fu will become dependent on the concentration of AAG.

Immunosuppressive drugs and pregnancy: Experimental and clinical data

Abstract THE REASONED choice of a drug results from the double evaluation of the expected benefit and the subsequent therapeutic risks. This becomes obviously more complicated when several drugs have to be given in combination for better effectiveness, as is the case for transplant patients. Therapeutic risks are therefore increased because either the side effects are the same in nature and act synergistically, or they simply become more numerous. They are also enhanced when drug indications coincide with particular conditions, one of them being pregnancy, which no doubt becomes a condition at risk in all transplant women. One has then to face the triple challenge to combine successfully altogether a right level of immunosuppression, a pregnancy that would work out normally, and the absence of fetal damage. A specific procedure does not exist today to systematically study what could be entitled a schools case of pharmacology. In fact, immunosuppressive treatments are established most of the time on the basis of empirical results, which means that there is only a narrow margin left for an attempt to modify therapeutic protocols that have been already stated that way. Immunosuppressant drugs also frequently, even constantly, develop side effects such as renal insufficiency and hypertension in the mother and prematurity in the fetus. With that in mind, we here will state the pharmacological basis for the use of immunosuppressants in posttransplant pregnant women, in order to provide not only for the mothers safety but also to prevent both the fetus (F1) and second generation (F2) from drug injury. In that view, we have designed a step-by-step critical analysis that addresses the various pharmacological parameters of immunosuppressants that may be used during pregnancy. Our evaluation has been made on the basis of toxicologic, pharmacodynamic, and pharmacokinetic criteria in the light of pregnancy itself and its most frequently associated pathological states.

Differential effects of zidovudine and zidovudine triphosphate on mitochondrial permeability transition and oxidative phosphorylation

The effects of zidovudine (ZDV) and zidovudine triphosphate (ZDV‐3P) on Ca2+‐induced mitochondrial permeability transition (MPT), respiratory control ratio (RCR) and ATP synthesis have been investigated on isolated rat liver mitochondria. ZDV slightly but significantly decreased RCR and ATP synthesis but was ineffective in inhibiting MPT. In contrast, ZDV‐3P did not alter RCR and ATP synthesis but strongly inhibited MPT (IC50=3.0±0.9 μM). The effect of ZDV‐3P on mitochondrial swelling required a preincubation time. When incubated 10 min with mitochondria, ZDV‐3P (8 μM) totally inhibited the rate of swelling. ADP, ATP and atractyloside, which are agents known to interact with the mitochondrial adenine nucleotide carrier (ANC), antagonized the effect of ZDV‐3P on mitochondrial swelling. Indeed, the IC50 value of ZDV‐3P increased from 3.0 to 17.4, 93.6 and 66.5 μM, in the presence of 20 μM, ADP, ATP or atractyloside, respectively. ZDV‐3P did not displace [3H]‐ATP from its mitochondrial binding site(s) whereas ADP and atractyloside did, suggesting that ZDV‐3P and [3H]‐ATP do not share the same binding sites. ZDV‐3P did not affect either mitochondrial respiration or ATP synthesis but inhibited Ca2+‐dependent mitochondrial swelling. It was concluded that mitochondrial toxic effects observed during the chronic administration of ZDV cannot be related to its active metabolite (ZDV‐3P).

Nimesulide binding to components within blood.

SummaryThe binding of nimesulide within human serum to isolated proteins and to erythrocytes was studied by equilibrium dialysis/Within the range of therapeutic concentrations, nimesulide was 99% bound to serum involving a nonsaturated process (NKA = 91). This binding was almost identical to binding of nimesulide to serum albumin (NKA = 95). Physiological concentrations of free fatty acids did not affect binding of nimesulide to serum albumin. The retention of nimesulide by erythrocytes suspended in buffer was moderate (67%), although in whole blood no erythrocyte binding was observed because of the greater affinity of this drug for serum. Over the range of therapeutic concentrations (2.5 to 63 μmol/L), the free fraction of nimesulide in serum remains constant. Serum binding was decreased in samples obtained from patients with renal failure or hepatic cirrhosis associated with hypoalbuminaemia and hyperbilirubinaemia, respectively. At therapeutic concentrations, the binding of nimesulide was unaffected by warfarin, cefoperazone, furosemide (frusemide), glibenclamide, tamoxifen or digitoxin. However, valproic acid and fenofibrate (80 μmol/L) may displace nimesulide. 4-Hydroxy-nimesulide, the principal metabolite, significantly increased the free fraction of nimesulide. Although methotrexate had no effect on the free fraction of nimesulide, the free fraction of methotrexate was significantly increased in the presence of nimesulide.The present study also demonstrated 2 distinct nimesulide binding sites (site I and site II) on serum albumin (10 μmol/L) with different affinities: site II KA = 3.57 × 105 L/mol and site I Ka = 1.24 × 105 L/mol. Interaction studies using markers that bind specifically to site I (warfarin and azapropazone) and site II (diazepam and ibuprofen) indicated that nimesulide binds to site II with higher affinity and to a lesser extent to site I.