Geneviève Ubeaud-Séquier

The Enzymatic Basis of Drug-Drug Interactions with Systemic Triazole Antifungals

Drug-drug interactions are a recurring problem in immunocompromised patients treated with triazole antifungals. While the introduction of new antifungals has expanded opportunities for lowering drug toxicity, virtually all antifungal regimens carry the risk of pharmacokinetic and pharmacodynamic interaction. This review presents the published data on molecular determinants (enzymes, transporters, orphan nuclear receptors) of systemic triazole pharmacokinetics in humans, including itraconazole, fluconazole, voriconazole and posaconazole. Systemic triazoles are inhibitors of cytochrome P450 (CYP) isozymes, such as CYP3A4, CYP2C9 and CYP2C19, to varying degrees. In addition, some are substrates and/or inhibitors of drug transporters such as multidrug resistance-1 gene product, P-glycoprotein, or breast cancer resistance protein. The interactions of triazole antifungals can be divided into the following categories: modifications of antifungal pharmacokinetics by other drugs, modifications of other drug pharmacokinetics by antifungals, and two-way interactions. These features are the basis of most interactions that occur during triazole therapy.

Quercetin and naringenin transport across human intestinal Caco-2 cells

Objectives Flavonoids are phenolic compounds found in most edible fruits and vegetables. Previous studies have demonstrated their biological and beneficial effects on human health. However, their bioavailability and, in particular, their intestinal absorption mechanism have not yet been clearly identified. The aim of our work was to quantify and to characterize in vitro the nature of the transport of two flavonoids distinguished by their physicochemical and pharmacological properties: quercetin, a flavan‐3‐ol, and naringenin, a flavanone.

Drug-Drug Interactions of Triazole Antifungal Agents in Multimorbid Patients and Implications for Patient Care

Drug interactions occur frequently with triazole antifungal agents because of their properties as inhibitors of 1 or more phase 1 (cytochrome P450) biotransformation enzymes and, possibly, as inhibitors or substrates of a phase 2 biotransformation enzyme or transporter protein. Multimorbid patients, including those with hematologic malignancies or other cancers, hematopoietic stem cell or organ transplant recipients, patients infected with the human immunodeficiency virus, and those in the intensive care unit, are at increased risk for drug interactions because they typically require several concomitant medications. They may also be extremely vulnerable to the clinical signs and symptoms of drug interactions. This review describes clinically significant drug interactions most frequently seen in multimorbid patients who receive systemic therapy with triazole antifungals for the prophylaxis or treatment of invasive fungal infections; including interactions with corticosteroids, immunosuppressants, anti-infective drugs, benzodiazepines, opioid analgesics, statins, anticoagulants, anticonvulsants, and drugs affecting gastric pH. The review also describes recommendations concerning contraindications and dose-modification strategies. The azoles differ markedly in their pharmacokinetic and antifungal properties, safety and tolerability, and drug-interaction profiles. Many drug interactions can be prevented if clinicians are thoroughly familiar with the pharmacokinetic profiles of different azoles, follow contraindications and dose-modification recommendations, and switch azoles when possible to achieve the best combination of clinical efficacy and safety. Therapeutic drug monitoring can help optimize treatment and prevent underdosing or overdosing of drugs. Education of patients and their families about signs and symptoms of possible drug interactions is also beneficial.

Adherence to recommendations for the use of antifungal agents in a tertiary care hospital

OBJECTIVES The aim of our study was to assess the adherence to labelling and international guidelines for antifungal prescribing. METHODS A retrospective study was performed in intensive care units in addition to the oncology and haematology department, which covered 70% of antifungal consumption at Hautepierre Hospital, Strasbourg, France. On reviewing medical charts, the antifungal prescription was examined in relation to the recommendations of indication, dosage, risk of drug-drug interactions and, where appropriate, antifungal susceptibility testing. Treatments were considered appropriate, inappropriate or debatable. RESULTS Between January and April 2007, 199 treatments were given for 179 different episodes in 133 adult patients. Treatments were prescribed for pre-emptive or targeted therapy (n = 90, with 60 for candidiasis, 26 for aspergillosis and 4 for other mould diseases), empirical therapy (n = 17) and primary (n = 81) or secondary (n = 11) prophylaxis. Fluconazole accounted for 67% of prescriptions, followed by voriconazole (19%), caspofungin (10%), posaconazole (2%), conventional or liposomal amphotericin B (2%), itraconazole (<1%) and terbinafine (<1%). Indication and dosage were found to be appropriate in 65% and 62% of cases, inappropriate in 22% and 21%, and debatable in 13% and 17%, respectively. The overall (by combining all assessment criteria) rate of inappropriate use was 40%. The overall survival rate at 12 weeks was highest in patients receiving appropriate therapy (81% versus 72% and 68% in the debatable and inappropriate therapy groups, respectively), with between-group differences not being significant (P = 0.49). CONCLUSIONS Our evaluation revealed a high proportion of inappropriate or debatable use of antifungal agents, while highlighting significant issues, such as inadequate dosage or indications.

Erlotinib: another candidate for the therapeutic drug monitoring of targeted therapy of cancer? A pharmacokinetic and pharmacodynamic systematic review of literature.

Abstract: Erlotinib is currently marketed at fixed standard dosage against pancreatic cancer and non–small-cell lung carcinoma. However, erlotinib pharmacokinetics (PK) is characterized by significant variability that may affect efficacy and tolerability. The aim of this review is to assess evidence that would justify therapeutic drug monitoring (TDM) and provide key information for the interpretation of erlotinib plasma concentrations. Literature was systematically reviewed to evaluate the standard criteria defining the potential clinical usefulness of TDM. Assessment was focused on the existence of unpredictable and wide PK variability and of consistent PK–pharmacodynamic relationships. PK parameters actually show marked variability (apparent clearance estimated to 4.85 ± 4.71 L/h, elimination half-life to 21.86 ± 28.35 hours, and apparent volume of distribution to 208 ± 133 L). Many covariates influence these parameters (CYP3A4 inducers or inhibitors, food, age, liver impairment), but most sources of variability still have to be identified. Some studies have demonstrated a relationship between exposure to erlotinib and clinical outcomes or skin toxicity. Erlotinib activity and target concentrations furthermore depend on tumor characteristics (eg, mutations on epidermal growth factor receptor and on K-ras). These results are in favor of TDM in addition to treatment adjustment for tumor biomarkers, but prospective clinical trials validating its clinical benefits are lacking. This review provides all the relevant information available to assist clinical interpretation of erlotinib plasma measurements. PK percentile curves and consideration to covariates yield information on whether a concentration measured is expected, whereas half maximal inhibitory concentration values determined in vitro provide preliminary insights on target concentration values to reach. Eventually, dosage adaptation might be considered in patients with intolerable toxicity because of excessive plasma levels or conversely nonresponse imputable to insufficient exposure.

Mécanismes des interactions médicamenteuses d’origine pharmacocinétique

Pharmacokinetic drug-drug interactions occur when a drug alters the disposition (absorption, distribution, elimination) of a coadministered agent. Pharmacokinetic interactions may result in the increase or the decrease of plasma drug concentrations. These modifications are variable in intensity but can lead to contraindications of the association. The mechanisms of pharmacokinetic interactions involve drug metabolizing enzymes, drug transporters and orphan nuclear receptors that regulate at the transcriptional level the expression of enzymes and transporters. The increase of drug plasma concentrations is generally related to the inhibition of enzymes and/or drug transport. The decrease of drug concentrations reflects the activation of orphan nuclear receptors by inducers that lead to the increase of the expression of enzymes and drug transporters. Inhibition of drug metabolism or transport is quite immediate (24-48h) while induction is a slower process (7-10 days). Complex situations may be observed with drugs that are both inducers and inhibitors (rifampin, ritonavir). They can cause the decrease and the increase of the exposure of the combined agent depending on the duration of the association.

The Pharmacokinetics of Ropivacaine After Intraperitoneal Administration: Instillation Versus Nebulization

BACKGROUND: Intraperitoneal local anesthetic administration provides perioperative analgesia during laparoscopic procedures. We compared the pharmacokinetics of intraperitoneal ropivacaine administered by instillation or nebulization. METHODS: A crossover study was performed on 5 pigs under standardized general anesthesia with a carbon dioxide pneumoperitoneum of 12 mm Hg for 1 hour. Each animal, acting as its own control, was studied twice with an 8-day interval and received, in a randomized sequence, 3 mg/kg ropivacaine either by intraperitoneal instillation at the time of pneumoperitoneum exsufflation or by continuous nebulization in the carbon dioxide insufflation tubing. Arterial blood samples were taken every 10 minutes up to 120 minutes, and then hourly up to 6 hours. Ropivacaine concentrations were measured using high-performance liquid chromatography with ultraviolet-visible detection. The plasma-free fraction was evaluated after plasma ultracentrifugation. Pharmacokinetic parameters were calculated using both noncompartmental and compartmental analysis. The mean values were compared using the Student t test, or Wilcoxon test for paired series. RESULTS: The data were described by a 1-compartment model for both ropivacaine administration techniques, with a delay of 10 minutes for the nebulization group. The maximal ropivacaine concentrations were 0.96 &mgr;g/mL for the nebulization group and 0.92 &mgr;g/mL for the instillation group (P = 0.66). The ropivacaine absorption constant was lower in the nebulization group (0.043 vs 0.083 min−1, P = 0.02). There were no differences in the elimination half-life, elimination constant, mean total body clearance, distribution volume, mean area under the curve, and mean residence time. The free fraction of ropivacaine was also similar in the 2 groups. CONCLUSIONS: The pharmacokinetic profile of ropivacaine nebulization is similar to direct intraperitoneal instillation, but with a lower absorption rate.

Implication of hepatic transporters (MDR1 and MRP2) in inflammation‐associated idiosyncratic drug‐induced hepatotoxicity investigated by microvolume cytometry

Idiosyncratic drug‐induced hepatotoxicity accounts for about 13% of all cases of acute liver failure, therefore cited as the most frequent reason for post‐marketing drug withdrawal. Despite this, the underlying mechanisms remain poorly understood due to lack in adequate screening assays and predictive in vitro models. Hepatic transporters play a crucial role in the absorption, distribution, and elimination of both endogenous substrates and xenobiotics. Defects in transporter function can lead to altered drug disposition, including toxicity and loss of efficacy. Inflammation is one condition for demonstrated variable drug response, attributed in part, to changes in function of drug transporters. The present study investigates the implication of two important hepatic transporters (MDR1 and MRP2) in idiosyncratic drug‐induced hepatotoxicity in the presence and absence of an inflammatory context. The synergistic effect of idiosyncratic drugs (Trovafloxacin, nimesulide, telithromycin, and nefazodone) and inflammatory stimuli (TNF‐α + LPS) on the efflux activity of hepatic transporters was studied using microvolume cytometry. Our results demonstrated on the one hand that both MDR1 and MRP2 are variably implicated in idiosyncratic drug‐induced liver injury and on the other hand that the occurrence of an inflammatory reaction during idiosyncratic drug therapy can noticeably modulate this implication. In the absence of an inflammatory stress, none of the four tested drugs modulated the efflux activity of MRP2; nevertheless telithromycin and nefazodone inhibited the efflux activity of MDR1. Upon occurrence of an inflammatory stress, the inhibitory potential of trovafloxacin, nimesulide, and nefazodone on the efflux activity of MRP2 was noticeably revealed, while the telithromycin and nefazodone‐induced inhibition of MDR1 was clearly attenuated. Knowledge of underlying mechanisms may significantly contribute to elimination of potential hepatotoxic drugs long before marketing and to prevention of drug‐induced hepatotoxicity.

Analogues of the marine alkaloids oroidin, clathrodin, and hymenidin induce apoptosis in human HepG2 and THP-1 cancer cells

The marine alkaloids clathrodin, oroidin, and hymenidin, which were isolated from Agelas sponges, possess diverse biological activities. Herein, we describe the design of a library of their analogues and the evaluation of their apoptosis-inducing activities against the human hepatocellular carcinoma HepG2 and acute monocytic leukaemia THP-1 cell lines. The screening of the complete library of 96 compounds using the HepG2 cell line allowed us to determine key structural elements and physicochemical properties that are responsible for the apoptosis-inducing activity. The indole-based compounds 24c, 28c, 29c, and 34c were found to be the most potent inducers of apoptosis in HepG2 and THP-1 cell lines with EC50 values in the low micromolar range. Cell cycle analysis assays confirmed that compounds 24c, 28c, 29c, and 34c induce the apoptosis of THP-1 cells at 25 μM, which highlights these oroidin analogues as interesting candidates for further evaluation of their anticancer activity.

Combining 2D angiogenesis and 3D osteosarcoma microtissues to improve vascularization

Abstract Angiogenesis is now well known for being involved in tumor progression, aggressiveness, emergence of metastases, and also resistance to cancer therapies. In this study, to better mimic tumor angiogenesis encountered in vivo, we used 3D culture of osteosarcoma cells (MG‐63) that we deposited on 2D endothelial cells (HUVEC) grown in monolayer. We report that endothelial cells combined with tumor cells were able to form a well‐organized network, and that tubule‐like structures corresponding to new vessels infiltrate tumor spheroids. These vessels presented a lumen and expressed specific markers as CD31 and collagen IV. The combination of 2D endothelial cells and 3D microtissues of tumor cells also increased expression of angiogenic factors as VEGF, CXCR4 and ICAM1. The cell environment is the key point to develop tumor vascularization in vitro and to be closer to tumor encountered in vivo. Graphical abstract Figure. No caption available. HighlightsCombining 2D endothelial cells/3D tumor cells leads to a well‐organized network.This network consists of tubule‐like structures able to infiltrate 3D tumor.These vessels present a lumen and express specific marker as CD31 and Collagen IV.Combined 2D/3D strategy allows to an increased expression of angiogenic factors.