QT time prolongation
Adverse drug events
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Explanations of the substances for patients
We have no additional warnings for the combination of lopinavir and torasemide. Please also consult the relevant specialist information.
|Torasemide||1 [1,3.85] 1,2||1|
The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. We do not expect any change in exposure for lopinavir, when combined with torasemide (100%). We do not expect any change in exposure for torasemide, when combined with lopinavir (100%). The AUC is between 100% and 385% depending on the CYP2C9
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
The bioavailability of lopinavir is unknown. Protein binding [ Pb ] is not known. The metabolism mainly takes place via CYP3A4 and the active transport takes place in particular via PGP.
Torasemide has a mean oral bioavailability [ F ] of 80%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather short at 3.5 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is very strong at 99% and the volume of distribution [ Vd ] is small at 15 liters. Since the substance has a low hepatic extraction rate of 0.02, displacement from protein binding [Pb] in the context of an interaction can lead to increased exposure. The metabolism takes place via CYP2C8 and CYP2C9, among others and the active transport takes place in particular via OATP1B1.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither lopinavir nor torasemide increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø|
Rating: According to our knowledge, neither lopinavir nor torasemide increase anticholinergic activity.
QT time prolongation
Rating: In combination, lopinavir and torasemide can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||lop||tor|
|Abdominal pain||1.0 %||n.a.||+|
|Hearing loss||0.0 %||n.a.||0.0|
|Toxic epidermal necrolysis||0.0 %||n.a.||0.0|
Thromboembolic disorder: torasemide
Based on your answers and scientific information, we assess the individual risk of undesirable side effects. These recommendations are intended to advise professionals and are not a substitute for consultation with a doctor. In the restricted test version (alpha), the risk of all substances has not yet been conclusively assessed.
Abstract: Torasemide is a new loop diuretic that potentially may have renal tubular effects from both the blood and urinary sides of the nephron. We assessed its pharmacokinetics and pharmacodynamics in eight normal subjects administering intravenous doses of 5, 10, and 20 mg compared with 40 mg furosemide. We assessed the effect of probenecid on response to the 20 mg dose. A dose intermediate to the 10 and 20 mg doses appeared equally natriuretic to 40 mg furosemide. Although total clearance was the same with all doses (about 0.45 ml/min/kg), renal clearance and the fraction of unchanged drug appearing in the urine decreased with higher doses raising the question of saturable renal secretion. Urinary dose-response curves showed torasemide to be five times as potent as furosemide. Probenecid pretreatment decreased both urine volume (P = 0.0016) and sodium excretion (P = 0.0003), implying that delivery of drug to the urinary side of the nephron is the major determinant of response.
Abstract: The new loop diuretic torasemide belongs to the pyridine sulfonylurea class. It is well absorbed and yields a bioavailablity of about 80% in healthy individuals, even higher in patients with oedema. This is roughly double that of the 'classical' loop diuretic furosemide (frusemide) [26 to 65%]. Torasemide is highly bound to protein (99%) as is furosemide. The volume of distribution of torasemide was determined as 0.2 L/kg as compared with 0.11 to 0.18 L/kg for furosemide. Torasemide undergoes extensive hepatic metabolism; only 20% of the parent drug is recovered unchanged in the urine. For comparison only 10 to 20% of furosemide undergoes phase II metabolisation (to the glucuronide). In chronic renal failure the renal clearance of torasemide decreased in proportion to the decrease of the patients' glomerular filtration rate, whereas the total plasma clearance (3 times that of the renal clearance) appeared to be independent of renal function. As expected, the renal excretion of torasemide metabolites is significantly retarded in renal disease. The pharmacokinetics of torasemide are significantly influenced by liver disease. Total plasma clearance of torasemide was reduced to about half of that found in the control group, yielding an increase in elimination half-life. A greater than normal fraction of torasemide was recovered in the urine of patients with cirrhosis. In contrast, the kinetics of furosemide appeared to depend more on kidney function than on liver disease. The pharmacodynamics of torasemide are principally the same as those reported from conventional loop diuretics due to their interference with one binding site in the thick ascending limb of Henle's loop, the Na+:K+:2Cl- carrier. The maximum natriuretic effect of all loop diuretics amounts to about 3 mmol Na+/min. Members of this class differ, however, with respect to their intravenous potency or affinity for the receptor, respectively: bumetanide > piretanide > torasemide > furosemide. So far, the only loop diuretic which has been shown to effectively lower high blood pressure is torasemide. This effect occurs at the low dose of 2.5 mg/day.
Abstract: No Abstract available
Abstract: BACKGROUND: Torasemide is frequently used for the treatment of hypertension and heart failure. However, the determinants of torasemide pharmacokinetics in patients during steady-state conditions are largely unknown. We therefore explored the impact of genetic polymorphisms of cytochrome P450 (CYP) 2C9 (CYP2C9) and organic anion transporting polypeptide (OATP) 1B1 (SLCO1B1), gender, and the effects of losartan and irbesartan comedication on the interindividual variability of steady-state pharmacokinetics of torasemide. PATIENTS AND METHODS: Twenty-four patients receiving stable medication with torasemide 10 mg once daily and with an indication for additional angiotensin II receptor blocker (ARB) treatment to control hypertension or to treat heart failure were selected. Blood samples were taken before torasemide administration and 0.5, 1, 2, 4, 8, 12 and 24 hours after administration. After this first study period, patients received either irbesartan 150 mg (five female and seven male patients aged 69+/-8 years) or losartan 100 mg (two female and ten male patients aged 61+/-8 years) once daily. After 3 days of ARB medication, eight blood samples were again collected at the timepoints indicated above. The patients' long-term medications, which did not include known CYP2C9 inhibitors, were maintained at a constant dose during the study. All patients were genotyped for CYP2C9 (*1/*1 [n=15]; *1/*2 [n = 4]; *1/*3 [n=5]) as well as for SLCO1B1 (c.521TT [n=13]; c.521TC [n=11]). RESULTS: Factorial ANOVA revealed an independent impact of the CYP2C9 genotype (dose-normalized area under the plasma concentration-time curve during the 24-hour dosing interval at steady state [AUC(24,ss)/D]: *1/*1 375.5+/-151.4 microg x h/L/mg vs *1/*3 548.5+/-271.6 microg x h/L/mg, p=0.001), the SLCO1B1 genotype (AUC(24,ss)/D: TT 352.3+/-114 microg x h/L/mg vs TC 487.6+/-218.4 microg x h/L/mg, p<0.05) and gender (AUC(24,ss)/D: males 359.5+/-72.2 microg x h/L/mg vs females 547.3+/-284 microg x h/L/mg, p<0.01) on disposition of torasemide. Coadministration of irbesartan caused a 13% increase in the AUC(24,ss)/D of torasemide (p=0.002), whereas losartan had no effect. CONCLUSION: This study shows that the CYP2C9*3 and SLCO1B1 c.521TC genotype and female gender are significant and independent predictors of the pharmacokinetics of torasemide. Coadministration of irbesartan yields moderate but significant increases in the torasemide plasma concentration and elimination half-life.
Abstract: On the basis of a single clinical trial in first-line treatment, the atazanavir and ritonavir combination appears to be no more effective than the fixed-dose combination of lopinavir and ritonavir. The adverse effect profiles were slightly different, but atazanavir carries a troubling risk of torsades de pointes.
Abstract: BACKGROUND: Drug-induced torsades de pointes (TdP) is a complex regulatory and clinical problem due to the rarity of this sometimes fatal adverse event. In this context, the US FDA Adverse Event Reporting System (AERS) is an important source of information, which can be applied to the analysis of TdP liability of marketed drugs. OBJECTIVE: To critically evaluate the risk of antimicrobial-induced TdP by detecting alert signals in the AERS, on the basis of both quantitative and qualitative analyses. METHODS: Reports of TdP from January 2004 through December 2008 were retrieved from the public version of the AERS. The absolute number of cases and reporting odds ratio as a measure of disproportionality were evaluated for each antimicrobial drug (quantitative approach). A list of drugs with suspected TdP liability (provided by the Arizona Centre of Education and Research on Therapeutics [CERT]) was used as a reference to define signals. In a further analysis, to refine signal detection, we identified TdP cases without co-medications listed by Arizona CERT (qualitative approach). RESULTS: Over the 5-year period, 374 reports of TdP were retrieved: 28 antibacterials, 8 antifungals, 1 antileprosy and 26 antivirals were involved. Antimicrobials more frequently reported were levofloxacin (55) and moxifloxacin (37) among the antibacterials, fluconazole (47) and voriconazole (17) among the antifungals, and lamivudine (8) and nelfinavir (6) among the antivirals. A significant disproportionality was observed for 17 compounds, including several macrolides, fluoroquinolones, linezolid, triazole antifungals, caspofungin, indinavir and nelfinavir. With the qualitative approach, we identified the following additional drugs or fixed dose combinations, characterized by at least two TdP cases without co-medications listed by Arizona CERT: ceftriaxone, piperacillin/tazobactam, cotrimoxazole, metronidazole, ribavirin, lamivudine and lopinavir/ritonavir. DISCUSSION: Disproportionality for macrolides, fluoroquinolones and most of the azole antifungals should be viewed as 'expected' according to Arizona CERT list. By contrast, signals were generated by linezolid, caspofungin, posaconazole, indinavir and nelfinavir. Drugs detected only by the qualitative approach should be further investigated by increasing the sensitivity of the method, e.g. by searching also for the TdP surrogate marker, prolongation of the QT interval. CONCLUSIONS: The freely available version of the FDA AERS database represents an important source to detect signals of TdP. In particular, our analysis generated five signals among antimicrobials for which further investigations and active surveillance are warranted. These signals should be considered in evaluating the benefit-risk profile of these drugs.
Abstract: The human organic anion and cation transporters are classified within two SLC superfamilies. Superfamily SLCO (formerly SLC21A) consists of organic anion transporting polypeptides (OATPs), while the organic anion transporters (OATs) and the organic cation transporters (OCTs) are classified in the SLC22A superfamily. Individual members of each superfamily are expressed in essentially every epithelium throughout the body, where they play a significant role in drug absorption, distribution and elimination. Substrates of OATPs are mainly large hydrophobic organic anions, while OATs transport smaller and more hydrophilic organic anions and OCTs transport organic cations. In addition to endogenous substrates, such as steroids, hormones and neurotransmitters, numerous drugs and other xenobiotics are transported by these proteins, including statins, antivirals, antibiotics and anticancer drugs. Expression of OATPs, OATs and OCTs can be regulated at the protein or transcriptional level and appears to vary within each family by both protein and tissue type. All three superfamilies consist of 12 transmembrane domain proteins that have intracellular termini. Although no crystal structures have yet been determined, combinations of homology modelling and mutation experiments have been used to explore the mechanism of substrate recognition and transport. Several polymorphisms identified in members of these superfamilies have been shown to affect pharmacokinetics of their drug substrates, confirming the importance of these drug transporters for efficient pharmacological therapy. This review, unlike other reviews that focus on a single transporter family, briefly summarizes the current knowledge of all the functionally characterized human organic anion and cation drug uptake transporters of the SLCO and the SLC22A superfamilies.
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.