Intervallo QT lungo
Reazione avversa da farmaco (ADR)
Varianti ✨Per l'analisi computazionale dettagliata delle varianti, si prega di selezionare l'abbonamento standard a pagamento.
Informazioni dei farmaci per i pazienti
Non abbiamo ulteriori avvertenze per la co-somministrazione di astemizolo e nelfinavir. Si prega di consultare le informazioni specialistiche pertinenti.
I cambiamenti riportati in seguito all'esposizione corrispondono ai cambiamenti nell'area sottesa alla curva concentrazione plasmatica-tempo [ AUC ]. Non è stato possibile rilevare nessun tipo di cambiamento nell'esposizione alla astemizolo. Allo stato attuale non è possibile valutare come influisce la nelfinavir. Non è stato possibile rilevare nessun tipo di cambiamento nell'esposizione alla nelfinavir. Allo stato attuale non è possibile valutare come influisce la astemizolo.
I parametri farmacocinetici della popolazione media sono utilizzati come punto di partenza per calcolare i cambiamenti del singolo individuo esposto alle interazioni farmacologiche
La astemizolo ha una bassa biodisponibilità [ F ] orale, perciò nel corso di un interazione farmacologica la concentrazione plasmatica massima (Cmax) tende fortemente a cambiare. L'emivita [ t12 ] del farmaco è di 22 ore e la concentrazione allo stato stazionario [Css] si raggiunge dopo circa 88 ore. Il legame proteico [ Pb ] è forte al 97%. Tra l'altro, il metabolismo avviene rispettivamente attraverso gli enzimi CYP2D6 e CYP3A4..
La nelfinavir ha una significativa biodisponibilità [ F ] orale pari al 50%, perciò attraverso un'interazione farmacologica la concentrazione plasmatica massima [Cmax] tende a cambiare di poco. L'emivita [ t12 ] del farmaco è piuttosto breve in 4.25 ore e lo stato stazionario [Css] si raggiunge molto velocemente. Il legame proteico [ Pb ] è forte al 98% e il volume di distribuzione [ Vd ] è molto grande in 315 litri, Dato che il farmaco ha un basso tasso di estrazione epatico, lo spiazzamento del legame alle proteine plasmatiche [Pb] porta ad un aumento all'esposizione farmacologica. Tra l'altro, il metabolismo avviene rispettivamente attraverso gli enzimi CYP2C19, CYP2D6 e CYP3A4. e il trasporto attivo avviene parzialmente attraverso i trasportatori MRP4 e PGP.
|Effetti serotoninergici a||0||Ø||Ø|
Valutazione: Sulla base dei dati a nostra disposizione, né la astemizolo né la nelfinavir potenziano l'attività serotoninergica.
|Kiesel & Durán b||0||Ø||Ø|
Valutazione: Sulla base dei dati a nostra disposizione, né la astemizolo né la nelfinavir causano un aumento dell'attività anticolinergica.
Intervallo QT lungo
Valutazione: La co-somministrazione di astemizolo e nelfinavir potrebbe causare tachicardia ventricolare a torsione di punta.
Effetti collaterali generali
|Effetti collaterali||∑ frequenza||ast||nel|
|Diabete mellito||0.0 %||n.a.||0.01|
Abbiamo valutato il rischio individuale di effetti indesiderati in base alle risposte fornite ed alle informazioni scientifiche disponibili. Le informazioni contenute nel sito hanno esclusivamente scopo informativo e non sostituiscono il parere del medico. Si accomanda pertanto di chiedere sempre il parere del proprio medico curante e/o di specialisti riguardo qualsiasi indicazione riportata. Nella versione alpha test, il rischio di tutti i farmaci non è stato ancora completamente valutato.
Abstract: Astemizole is a long-acting, highly selective histamine1-receptor antagonist with minimal central and anticholinergic effects. Comparison studies have shown astemizole to be equal or superior to currently available antihistamines, beclomethasone nasal spray, and cromolyn sodium in relieving allergic symptoms of seasonal and perennial allergic rhinitis. Other uses include treatment of allergic conjunctivitis and chronic urticaria. Astemizole is not as effective for treatment of acute allergic symptoms because of its delayed onset of action. Astemizole and its active metabolite, desmethylastemizole, have long elimination half-lives permitting once-daily dosing. The incidence of sedation is lower than with conventional antihistamines, but increased appetite and weight gain do occur. Astemizole should be useful for both maintenance and prophylactic therapy in patients with chronic allergic conditions who cannot tolerate the sedative or anticholinergic effects of conventional antihistamines.
Abstract: Astemizole is an H1-histamine receptor antagonist with a long duration of action permitting once daily administration. Its efficacy in seasonal and perennial allergic rhinitis has been convincingly demonstrated, and several comparative studies suggest that astemizole is at least as effective as some other H1-histamine receptor antagonists. A few smaller studies have shown beneficial effects on the symptoms of allergic conjunctivitis and chronic urticaria (but not atopic dermatitis). While astemizole appears to share with other H1-histamine receptor antagonists a tendency to increase appetite and cause weight gain after prolonged use, it offers the important advantage of an absence of significant central nervous system depression or anticholinergic effects with usual doses. Thus, astemizole offers a worthwhile improvement in side effect profile over 'traditional' H1-histamine receptor antagonists, especially in patients bothered by the sedative effects of these drugs.
Abstract: An overdose of astemizole predisposes the myocardium to ventricular dysrhythmias, including torsades de pointes. Herein we describe a case of astemizole-induced torsades de pointes ventricular tachycardia and also review previous case reports in the literature. All the patients were young, and dysrhythmias developed only in those with corrected QT intervals greater than 500 ms. Although several mechanisms have been postulated, no clear explanation has been provided for why astemizole promotes myocardial dysrhythmias. Treatment of astemizole-induced torsades de pointes includes discontinuing use of astemizole, intravenous administration of magnesium sulfate and isoproterenol, temporary cardiac pacing, and, when necessary, direct current cardioversion. A cardiac cause of syncope or convulsions must not be overlooked, especially in patients taking H1 antagonists because they often have these symptoms before hospitalization or detection of torsades de pointes (or both).
Abstract: No Abstract available
Abstract: A 26 year-old woman was admitted to the hospital two hours after astemizole overdose. Electrocardiograph showed a prolonged QT interval. Torsade de pointes occurred 13 h after ingestion. Plasma levels of astemizole plus hydroxylated metabolites showed an apparent plasma half-life of 17 h. The possible occurrence of torsade de pointes in astemizole overdose, and the long elimination time of astemizole and hydroxylated metabolites, makes it necessary to maintain ECG monitoring until QT interval has returned to normal.
Abstract: AIMS: The aim of this study was to investigate the influence of chronic itraconazole treatment on the pharmacokinetics and cardiovascular effects of single dose astemizole in healthy subjects was studied. METHODS: Twelve male volunteers were taking orally 200 mg twice daily itraconazole or placebo for 14 days with a washout period of 4 weeks in between. Approximately 2 h after the morning dose of itraconazole or placebo on day 11, 10 mg astemizole was orally administered. The plasma concentrations of astemizole and desmethylastemizole were measured by radioimmunoassay up to 504 h after administration; electrocardiograms with analysis of the QTc interval were recorded up to 24 h post administration. RESULTS: Itraconazole treatment did not significantly change the peak concentration of astemizole (0.74 vs 0.81 ng ml-1) but it increased the area under the curve from 0 to 24 h (5.46 to 9.95 ng ml-1 h) and from 0 to infinity (17.4 to 48.2 ng ml-1 h), and the elimination half-life (2.1 to 3.6 days). The systemic bioavailability of desmethylastemizole was also increased. The QTc interval did not increase after astemizole administration and there was no difference in the QTc intervals between the itraconazole and placebo session. CONCLUSIONS: Chronic administration of itraconazole influences the metabolism of single dose astemizole in normal volunteers without changes of cardiac repolarization during the first 24 h after astemizole administration. However, the reduction in astemizole clearance under concomitant administration of itraconazole may result in a marked increase in astemizole plasma concentrations and QTc alterations during chronic combined intake of astemizole with itraconazole.
Abstract: Using a combination of iterative structure-based design and an analysis of oral pharmacokinetics and antiviral activity, AG1343 (Viracept, nelfinavir mesylate), a nonpeptidic inhibitor of HIV-1 protease, was identified. AG1343 is a potent enzyme inhibitor (Ki = 2 nM) and antiviral agent (HIV-1 ED50 = 14 nM). An X-ray cocrystal structure of the enzyme-AG1343 complex reveals how the novel thiophenyl ether and phenol-amide substituents of the inhibitor interact with the S1 and S2 subsites of HIV-1 protease, respectively. In vivo studies indicate that AG1343 is well absorbed orally in a variety of species and possesses favorable pharmacokinetic properties in humans. AG1343 (Viracept) has recently been approved for marketing for the treatment of AIDS.
Abstract: Second-generation histamine H1 receptor antagonists (antihistamines) have been developed to reduce or eliminate the sedation and anticholinergic adverse effects that occur with older H1 receptor antagonists. This article evaluates second-generation antihistamines, including acrivastine, astemizole, azelastine, cetirizine, ebastine, fexofenadine, ketotifen, loratadine, mizolastine and terfenadine, for significant features that affect choice. In addition to their primary mechanism of antagonising histamine at the H1 receptor, these agents may act on other mediators of the allergic reaction. However, the clinical significance of activity beyond that mediated by histamine H1 receptor antagonism has yet to be demonstrated. Most of the agents reviewed are metabolised by the liver to active metabolites that play a significant role in their effect. Conditions that result in accumulation of astemizole, ebastine and terfenadine may prolong the QT interval and result in torsade de pointes. The remaining agents reviewed do not appear to have this risk. For allergic rhinitis, all agents are effective and the choice should be based on other factors. For urticaria, cetirizine and mizolastine demonstrate superior suppression of wheal and flare at the dosages recommended by the manufacturer. For atopic dermatitis, as adjunctive therapy to reduce pruritus, cetirizine, ketotifen and loratadine demonstrate efficacy. Although current evidence does not suggest a primary role for these agents in the management of asthma, it does support their use for asthmatic patients when there is coexisting allergic rhinitis, dermatitis or urticaria.
Abstract: OBJECTIVE: To review the clinical pharmacology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage guidelines of nelfinavir mesylate. DATA SOURCE: A MEDLINE search restricted to English-language literature from January 1966 to February 1998 and an extensive review of journals was conducted to prepare this article. MeSH headings included protease inhibitors, nelfinavir mesylate, and AG1343. Abstracts presented at meetings and data submitted to the Food and Drug Administration (FDA) were also reviewed. DATA EXTRACTION: The data on efficacy, pharmacokinetics, adverse effects, and drug interactions were obtained from in vitro studies, as well as open-label and controlled trials. DATA SYNTHESIS: Nelfinavir inhibits HIV protease enzyme resulting in formation of immature and noninfectious virions. In combination with nucleoside reverse transcriptase inhibitors, nelfinavir is effective in reducing the viral load below the quantifiable limit (< 500 copies/mL) and increasing the mean CD4+ cell count. This antiviral effect is sustained at least over 21 months. The bioavailability of nelfinavir ranges from 20% to 80%, and it increases when nelfinavir is administered with food. Following multiple dosing of nelfinavir 750 mg three times daily, maximum concentration at steady-state was 3-4 micrograms/mL and minimum concentration was 1-3 micrograms/mL. The elimination half-life for nelfinavir ranges from three to five hours. Nelfinavir is primarily metabolized in the liver by the cytochrome P450 isoenzymes and excreted in the feces. Current dosing recommendations are 750 mg three times daily for adults and adolescents and 20-30 mg/kg/dose three times daily for children aged 2-13 years. Studies of twice-daily regimens in adults are being conducted and are promising. Use of nelfinavir as salvage therapy is also being studied. Some of the commonly reported adverse events of nelfinavir are diarrhea, nausea, vomiting, and abdominal pain. CONCLUSIONS: Despite the limited published data, the FDA has approved nelfinavir in combination therapy for the treatment of HIV infection. The choice of antiretroviral (ARV) regimens should be made based on the risk of disease progression as indicated by HIV RNA concentrations and CD4+ cell counts, patients' previous ARV experiences and responses, concomitant drug therapy, compliance history, underlying disease states, and adverse reaction history.
Abstract: A population pharmacokinetic analysis was conducted on nelfinavir in patients infected with human immunodeficiency virus (HIV) who were enrolled in a phase III clinical trial. The data consisted of 509 plasma concentrations from 174 patients who received nelfinavir at a dose of 500 or 750 mg three times a day. The analysis was performed using nonlinear mixed-effect modeling as implemented in NONMEM (version 4.0; double precision). A one-compartment model with first-order absorption best described the data. The timing and small number of early postdose blood levels did not allow accurate estimation of volume of distribution (V/F) and the absorption rate constant (k(a)). As a result, two models were used to analyze the data: model 1, in which oral clearance (CL/F), V/F, and k(a) were estimated, and model 2, in which V/F and k(a) were fixed to known values and only CL/F was estimated. Estimates of CL/F ranged from 41. 9 to 45.1 liters/h, values in close agreement with previous studies. Neither body weight, age, sex, race, dose level, baseline viral load, metabolite-to-parent drug plasma concentration ratio, history of liver disease, nor elevated results of liver function tests appeared to be significant covariates for clearance. The only significant covariate-parameter relationship was concomitant use of fluconazole on CL/F, which was associated with a modest reduction in interindividual variability of CL/F. Patients who received concomitant therapy with fluconazole had a statistically significant reduction in nelfinavir CL/F of 26 to 30%. Since serious dose-limiting toxicity and concentration-related toxicities are not apparent for nelfinavir, this effect of fluconazole is unlikely to be of clinical significance.
Abstract: AIMS: The aims of the present study were to investigate the metabolism of astemizole in human liver microsomes, to assess possible pharmacokinetic drug-interactions with astemizole and to compare its metabolism with terfenadine, a typical H1 receptor antagonist known to be metabolized predominantly by CYP3A4. METHODS: Astemizole or terfenadine were incubated with human liver microsomes or recombinant cytochromes P450 in the absence or presence of chemical inhibitors and antibodies. RESULTS: Troleandomycin, a CYP3A4 inhibitor, markedly reduced the oxidation of terfenadine (26% of controls) in human liver microsomes, but showed only a marginal inhibition on the oxidation of astemizole (81% of controls). Three metabolites of astemizole were detected in a liver microsomal system, i.e. desmethylastemizole (DES-AST), 6-hydroxyastemizole (6OH-AST) and norastemizole (NOR-AST) at the ratio of 7.4 : 2.8 : 1. Experiments with recombinant P450s and antibodies indicate a negligible role for CYP3A4 on the main metabolic route of astemizole, i.e. formation of DES-AST, although CYP3A4 may mediate the relatively minor metabolic routes to 6OH-AST and NOR-AST. Recombinant CYP2D6 catalysed the formation of 6OH-AST and DES-AST. Studies with human liver microsomes, however, suggest a major role for a mono P450 in DES-AST formation. CONCLUSIONS: In contrast to terfenadine, a minor role for CYP3A4 and involvement of multiple P450 isozymes are suggested in the metabolism of astemizole. These differences in P450 isozymes involved in the metabolism of astemizole and terfenadine may associate with distinct pharmacokinetic influences observed with coadministration of drugs metabolized by CYP3A4.
Abstract: Understanding drug interactions between antiretrovirals and opiate therapies may decrease toxicities and enhance adherence, with improved HIV outcomes in injection drug users. We report results of a clinical pharmacology study designed to examine the interaction of the protease inhibitor, nelfinavir, with methadone and LAAM (N = 48). Nelfinavir decreased methadone exposure, but no withdrawal was observed over the five day study period. LAAM and dinorLAAM concentrations were decreased, while norLAAM concentrations were increased, with minimal overall change in LAAM/metabolite exposure. Methadone and LAAM did not affect nelfinavir concentrations, but methadone decreased M8 metabolite exposure. While no toxicities were observed, clinicians should be aware of the potential for drug interactions when patients require treatment with nelfinavir and these opiate medications.
Abstract: OBJECTIVES: This study was designed to assess the bioequivalence between the commercial 250 mg nelfinavir tablet and the new 625 mg nelfinavir tablet (Roche) which was developed to reduce the daily pill burden for patients from 10 to 4 tablets in a nelfinavir 1250 mg twice daily regimen. METHODS: A total of 52 healthy male subjects were enrolled in this randomized four-period crossover study to receive single oral doses of 1250 mg nelfinavir administered as five commercial 250 mg tablets (reference formulation) and as two new 625 mg tablets (test formulation). Each of the two formulations were taken after an overnight fast and immediately after intake of a standard breakfast (820 kcal) on separate occasions. Blood samples were collected pre-dose and at appropriate intervals after drug administration. Plasma concentrations of nelfinavir and its main metabolite M8 were assayed by a validated LC-MS/ MS assay and the pharmacokinetics of nelfinavir and M8 were derived using standard non-compartmental analysis. RESULTS: The primary parameters for bioequivalence testing were the logarithmically transformed AUC(0-inf) and C(max) of nelfinavir taken from 50 subjects who completed all four treatments. Bioequivalence was accepted if the 90% confidence interval (CI) was contained entirely in the equivalence region (80%, 125%). In the fed state, this criterion was met for AUC (effect ratio = 95%; CI = 87%, 103%) and Cmax (effect ratio = 101%; CI = 94%, 109%) and bioequivalence of the two treatments could be concluded. In the fasted state, AUC clearly failed to meet the bioequivalence criteria (effect ratio = 73%; CI = 59%, 90%) and Cmax was borderline outside the lower acceptance region (effect ratio = 97%; CI = 79.6%, 118%). Therefore, bioequivalence could not be concluded under fasted condition. Food increased the systemic exposure to nelfinavir (as reflected by comparison of the logarithmically transformed AUC(0-inf) values under fed and fasted conditions) by six- and eight-fold after dosing with the 250 mg and the 625 mg tablet, respectively. CONCLUSIONS: Bioequivalence of the new 625 mg nelfinavir tablet relative to the commercial 250 mg tablet, at a dose of 1250 mg, was confirmed in the fed state but not under fasted conditions. As nelfinavir is recommended to be taken with food, the new tablet is well-suited to decrease the daily pill burden for patients on a nelfinavir twice daily regimen and to enhance patient's compliance and adherence.
Abstract: UNLABELLED: The effect of nelfinavir 1250 mg twice daily (b.i.d.) on the pharmacokinetics of methadone was determined in 14 HIV-negative methadone users. DESIGN: The methadone dose (20-140 mg/day) was stabilized and fixed for at least 1 month before nelfinavir (1250 mg b.i.d. for 8 days) was added to the regimen. The concentrations of methadone enantiomers were measured before and during nelfinavir treatment, and the concentrations of nelfinavir and its active metabolite, AG1402, were measured during nelfinavir treatment. Adverse events and withdrawal/intoxication symptoms were monitored throughout the study. RESULTS: Nelfinavir reduced the area under the concentration-time curve of R-methadone, and S-methadone by 43% and 51%, respectively. Nelfinavir and AG1402 concentrations were within the normal range of historical data, and no subject experienced withdrawal symptoms during the study or required dose adjustment during or after the study. CONCLUSIONS: Although nelfinavir reduced the plasma concentrations of both R- and S-methadone, it seems to have no impact on the maintenance dose of methadone. A routine reduction of methadone dose is not recommended when coadministered with nelfinavir.
Abstract: STUDY OBJECTIVES: To assess the effect of omeprazole on the multiple-dose (steady-state) pharmacokinetics and safety of nelfinavir, and to evaluate the safety and tolerability of nelfinavir when administered alone and with omeprazole. DESIGN: Open-label, two-period, single-fixed-sequence study. SETTING: Clinical research unit of a large, teaching hospital. PARTICIPANTS: Twenty healthy volunteers (mean age 26 +/- 9 yrs, range 18-48 yrs). Intervention. Subjects received nelfinavir 1250 mg every 12 hours for 4 days (period 1). After a 7-day washout period, subjects were coadministered nelfinavir 1250 mg every 12 hours and omeprazole 40 mg every 24 hours for 4 days (period 2). MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of nelfinavir and its active metabolite M8 were determined on day 4 of both periods. Plasma samples were assayed by a high-performance liquid chromatography-ultraviolet method for nelfinavir and M8 concentrations, and noncompartmental pharmacokinetic analysis was performed by using analytical software. In the presence of omeprazole, nelfinavir area under the concentration-time curve over the dosing interval (AUC(tau)), maximum observed plasma concentration (C(max)), and minimum observed plasma concentration (C(min)) were reduced by an average of 36%, 37%, and 39%, respectively, relative to administration of nelfinavir alone. The AUC(tau), C(max), and C(min) of M8 were reduced by an average of 92%, 89%, and 75%, respectively. The slopes of the terminal elimination phase of nelfinavir and M8 plasma concentration-time curves were similar between treatments. Nelfinavir was well tolerated when administered alone and when coadministered with omeprazole. CONCLUSION: The observed reduction in the systemic exposure to both nelfinavir and its active metabolite M8 after coadministration with omeprazole could result in loss of virologic control and potential emergence of drug resistance. Hence, omeprazole should not be coadministered to patients taking nelfinavir.
Abstract: This was a randomized, 4-way crossover, third-party-blinded study in 68 healthy subjects to assess the effect of nelfinavir on QTc interval. Treatments included (A) nelfinavir 1250 mg every 12 hours on days 1-4, (B) nelfinavir 1250 mg every 12 hours on days 1-3 plus 3125 mg on day 4, (C) placebo, and (D) moxifloxacin 400 mg every 24 hours on days 1-4. Pharmacokinetics and triplicate 12-lead electrocardiograms were performed over 12 hours on days 1 and 4. Time-matched, placebo-subtracted, baseline-adjusted changes in QT intervals with Fridericia's (QTcF) correction were determined following nelfinavir and moxifloxacin administration. Neither dose of nelfinavir had a clinically relevant effect on the QTcF interval on day 4 (primary endpoint) and day 1 because at every time point the upper 90% confidence limit was below 10 milliseconds and, furthermore, the mean difference was below 5 milliseconds. Additionally, there was no clinically relevant effect on QTcB (Bazett's correction), uncorrected QT, or the RR interval on days 1 or 4. Pharmacokinetics confirmed adequate systemic exposure to nelfinavir and moxifloxacin. While nelfinavir exposure was higher in poor compared with extensive metabolizers of CYP2C19 isozyme, there were no corresponding significant differences in QTcF change from placebo. At clinically relevant, doses nelfinavir is unlikely to cause QTc prolongation.
Abstract: BACKGROUND: The objective of this research was to identify the impact of genetic variants of P-glycoprotein (ABCB1) and cytochrome P450 (CYP) on nelfinavir pharmacokinetics and response to highly active antiretroviral therapy (HAART) in HIV-1-infected children. METHODS: HIV-1-infected children (n = 152) from Pediatric AIDS Clinical Trial Group 366 or 377 receiving nelfinavir as a component of HAART were evaluated. Genomic DNA was assayed for ABCB1 and CYP genetic variants using real-time polymerase chain reaction Nelfinavir oral clearance (CL/F), M8 to nelfinavir ratios, CD4 T cells, and HIV-1-RNA were measured during HAART. RESULTS: Nelfinavir CL/F and M8 to nelfinavir ratios were significantly associated with the CYP2C19-G681A genotypes (P < 0.001). Furthermore, the CYP2C19-G681A genotype was related to virologic responses at week 24 (P = 0.01). A multivariate analysis demonstrated that age (P = 0.03), concomitant protease inhibitor use (P < 0.001), and the CYP2C19-G681A genotype (P < 0.001) remained significant covariates associated with nelfinavir CL/F. CONCLUSIONS: CYP2C19 genotypes altered nelfinavir pharmacokinetics and the virologic response to HAART in HIV-1-infected children. These findings suggest that CYP2C19 genotypes are important determinants of nelfinavir pharmacokinetics and virologic response in HIV-1-infected children.
Abstract: Elevations in serum bilirubin during drug treatment may indicate global liver dysfunction and a high risk of liver failure. However, drugs also can increase serum bilirubin in the absence of hepatic injury by inhibiting specific enzymes/transporters. We constructed a mechanistic model of bilirubin disposition based on known functional polymorphisms in bilirubin metabolism/transport. Using physiologically based pharmacokinetic (PBPK) model-predicted drug exposure and enzyme/transporter inhibition constants determined in vitro, our model correctly predicted indinavir-mediated hyperbilirubinemia in humans and rats. Nelfinavir was predicted not to cause hyperbilirubinemia, consistent with clinical observations. We next examined a new drug candidate that caused both elevations in serum bilirubin and biochemical evidence of liver injury in rats. Simulations suggest that bilirubin elevation primarily resulted from inhibition of transporters rather than global liver dysfunction. We conclude that mechanistic modeling of bilirubin can help elucidate underlying mechanisms of drug-induced hyperbilirubinemia, and thereby distinguish benign from clinically important elevations in serum bilirubin.
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.