QT time prolongation
Adverse drug events
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Explanations of the substances for patients
|Pravastatin||1.45 [1.45,2.6] 1||1.42||1.02|
The changes in exposure mentioned relate to changes in the plasma concentration-time curve [AUC]. Pravastatin exposure increases to 145%, when combined with verapamil (142%) and amiodarone (102%). Verapamil exposure increases to 130%, when combined with amiodarone (130%). We cannot currently estimate the influence of pravastatin. We did not detect any change in exposure to amiodarone, when combined with pravastatin (100%). We cannot currently estimate the influence of verapamil.
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Pravastatin has a low oral bioavailability [ F ] of 18%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The terminal half-life [ t12 ] is rather short at 0.79 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is rather weak at 48.5% and the volume of distribution [ Vd ] is 34 liters in the middle range. which is why, with a mean hepatic extraction rate of 0.65, both liver blood flow [Q] and a change in protein binding [Pb] are relevant. About 47.0% of an administered dose is excreted unchanged via the kidneys and this proportion is seldom changed by interactions. The metabolism does not take place via the common cytochromes and the active transport takes place partly via BCRP, MRP2, MRP4, OATP1A2, OATP1B1, OATP2B1 and PGP.
Verapamil has a low oral bioavailability [ F ] of 26%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The terminal half-life [ t12 ] is rather short at 3.4 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is moderately strong at 91% and the volume of distribution [ Vd ] is very large at 616 liters, However, since the substance has a high hepatic extraction rate of 0.71, only changes in the liver blood flow [Q] are relevant. The metabolism takes place via CYP1A2, CYP2C8, CYP2C9 and CYP3A4, among others and the active transport takes place partly via OATP1A2 and PGP.
Amiodarone has a mean oral bioavailability [ F ] of 55%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather long at 1884 hours and constant plasma levels [ Css ] are only reached after more than 7536 hours. The protein binding [ Pb ] is 96% strong. The metabolism takes place via CYP2C8 and CYP3A4, among others and the active transport takes place in particular via PGP.
|Serotonergic Effects a||0||Ø||Ø||Ø|
Rating: According to our knowledge, neither pravastatin, verapamil nor amiodarone increase serotonergic activity.
Rating: According to our findings, neither pravastatin, verapamil nor amiodarone increase anticholinergic activity.
QT time prolongation
Rating: Amiodarone can trigger potentially torsades de pointes ventricular arrhythmias. We do not know of any QT-prolonging potential for pravastatin and verapamil.
General adverse effects
|Side effects||∑ frequency||pra||ver||ami|
|Musculoskeletal pain||14.4 %||14.4||n.a.||n.a.|
|Upper respiratory infection||12.7 %||12.7||n.a.||n.a.|
|Loss of appetite||6.5 %||n.a.||n.a.||6.5|
Ataxia (6.5%): amiodarone
Coordination problem (6.5%): amiodarone
Paresthesia (6.5%): amiodarone
Peripheral neuropathy: amiodarone
Pseudotumor cerebri: amiodarone
Blurred vision (6.5%): amiodarone
Optic neuritis: amiodarone
Visual loss: amiodarone
Peripheral edema (3.7%): verapamil
Orthostatic hypotension (2.3%): verapamil
Bradycardia: amiodarone, verapamil
Heart failure: amiodarone
Ventricular arrhythmia: amiodarone
Atrioventricular block: verapamil
Nasopharyngitis (3%): verapamil, pravastatin
Acute respiratory distress syndrome (2%): amiodarone
Pulmonary fibrosis: amiodarone
Hyperthyroidism (2%): amiodarone
Stevens johnson syndrome: amiodarone
Toxic epidermal necrolysis: amiodarone
Feeling nervous: verapamil
Hypersensitivity reaction: amiodarone
Renal failure: amiodarone
Rupture of tendon: pravastatin
Based on your
Abstract: Pravastatin sodium, a competitive inhibitor of HMG-CoA reductase, is a new orally effective hypocholesterolaemic agent. In a two-way crossover study, eight healthy male subjects each received an intravenous and an oral dose of [14C]-pravastatin sodium. The oral absorption of [14C] activity from pravastatin sodium was about 34% and the oral bioavailability was about 18%, suggesting first-pass metabolism of pravastatin. After the intravenous dose, the recovery of radioactivity averaged 60% and 34% in urine and faeces, respectively. Corresponding values were 20% (urine) and 71% (faeces) for the oral dose. The estimated average plasma elimination half-life of pravastatin was 0.8 and 1.8 h for the intravenous and oral routes, respectively. The average values for total and renal clearances were 13.5 and 6.3 ml min-1 kg-1, respectively, and the steady-state volume of distribution averaged 0.51 kg-1. These results suggest that both kidney and liver are important sites of elimination for pravastatin.
Abstract: The effects of multiple doses of cimetidine on single-dose verapamil kinetics were studied in nine healthy men. Baseline hepatic blood flow was estimated by indocyanine green elimination on day 1. On day 2, the subjects received verapamil, 10 mg iv, after which the plasma concentration-time profile was determined. After a 2-day washout, cimetidine, 300 mg, was taken by mouth four times a day for 5 days. The indocyanine green study was repeated on day 9 and verapamil was taken on day 10. Cimetidine reduced verapamil clearance by 21% and increased the elimination t1/2 by 50%. The volume of distribution at steady state did not change. Cimetidine increased hepatic blood flow in some subjects, while decreasing it in others. There was no correlation between individual changes in verapamil clearance and hepatic blood flow. These data indicate that cimetidine reduces verapamil clearance by mechanism(s) other than a change in hepatic blood flow or volume of distribution.
Abstract: The pharmacokinetics of verapamil was studied in patients with end-stage chronic renal failure and in normal subjects after i.v. injection of 3 mg and a single oral dose of 80 mg. Plasma levels of verapamil and its active metabolite norverapamil were measured by HPLC. After i.v. injection, the terminal phase half-life and total plasma clearance of verapamil in both groups were similar. Haemodialysis did not change the time course of plasma verapamil levels after i.v. administration. After a single oral dose, the plasma levels of verapamil and norverapamil in both groups of subjects were similar. Subsequently, normal volunteers and patients with renal failure were treated for 5 days with oral verapamil 80 mg t.d.s. There was no difference between the 2 groups of subjects in the trough and peak levels of verapamil or of norverapamil. Intravenous and oral administration of the calcium channel blocking agent had similar effects on blood pressure, heart rate and the PR-interval in the electrocardiogram in both groups. The study demonstrated that the disposition of verapamil was similar in normal subjects and in patients with renal failure.
Abstract: The pharmacokinetics of (+)-, (-)-, and (+/-)-verapamil were studied in five healthy volunteers following i.v. administration of the drugs. Pronounced differences of the various pharmacokinetic parameters were observed between the (-)- and (+)-isomers. The values for CL, V, Vz, and Vss of the (-)-isomer were substantially higher as compared to the (+)-isomer, whereas terminal t 1/ 2Z was nearly identical for both isomers. No dose dependency of the pharmacokinetics could be observed in two subjects who received 5, 7.5 and 10 mg of (-)- and 5, 25 and 50 mg of (+)-verapamil. Protein binding for the two isomers was also different. The fu of (-)- (0.11) was almost twice as much as that of (+)-verapamil (0.064). Pharmacokinetic parameters of (+/-)-verapamil, which was administered to three subjects who had received (+)- and (-)-verapamil, were very similar to the averaged values of the isomers given separately. Due to the higher CL of (-)-verapamil the extraction ratio of the (-)-isomer is substantially higher. Thus, it can be anticipated that following oral administration of racemic verapamil bioavailability of (-)-verapamil will be substantially less. Since the (-)-isomer is more potent than the (+)-isomer, the present findings could explain the reported differences in the concentration-effect relationship after i.v. and oral administration of racemic verapamil.
Abstract: Amiodarone is considered to be safe in patients with prior QT prolongation and torsades de pointes taking class I antiarrhythmic agents who require continued antiarrhythmic drug therapy. However, the safety of amiodarone in advanced heart failure patients with a history of drug-induced torsades de pointes, who may be more susceptible to proarrhythmia, is unknown. Therefore, the objective of this study was to assess amiodarone safety and efficacy in heart failure patients with prior antiarrhythmic drug-induced torsades de pointes. We determined the history of torsades de pointes in 205 patients with heart failure treated with amiodarone, and compared the risk of sudden death in patients with and without such a history. To evaluate the possibility that all patients with a history of torsades de pointes would be at high risk for sudden death regardless of amiodarone treatment, we compared this risk in patients with a history of torsades de pointes who were and were not subsequently treated with amiodarone. Of 205 patients with advanced heart failure, 8 (4%) treated with amiodarone had prior drug-induced torsades de pointes. Despite similar severity of heart failure, the 1-year actuarial sudden death risk was markedly increased in amiodarone patients with than without prior torsades de pointes (55% vs 15%, p = 0.0001). Similarly, the incidence of 1-year sudden death was markedly increased in patients with prior torsades de pointes taking amiodarone compared with such patients who were not subsequently treated with amiodarone (55% vs 0%, p = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Twenty-nine drugs of disparate structures and physicochemical properties were used in an examination of the capability of human liver microsomal lability data ("in vitro T(1/2)" approach) to be useful in the prediction of human clearance. Additionally, the potential importance of nonspecific binding to microsomes in the in vitro incubation milieu for the accurate prediction of human clearance was investigated. The compounds examined demonstrated a wide range of microsomal metabolic labilities with scaled intrinsic clearance values ranging from less than 0.5 ml/min/kg to 189 ml/min/kg. Microsomal binding was determined at microsomal protein concentrations used in the lability incubations. For the 29 compounds studied, unbound fractions in microsomes ranged from 0.11 to 1.0. Generally, basic compounds demonstrated the greatest extent of binding and neutral and acidic compounds the least extent of binding. In the projection of human clearance values, basic and neutral compounds were well predicted when all binding considerations (blood and microsome) were disregarded, however, including both binding considerations also yielded reasonable predictions. Including only blood binding yielded very poor projections of human clearance for these two types of compounds. However, for acidic compounds, disregarding all binding considerations yielded poor predictions of human clearance. It was generally most difficult to accurately predict clearance for this class of compounds; however the accuracy was best when all binding considerations were included. Overall, inclusion of both blood and microsome binding values gave the best agreement between in vivo clearance values and clearance values projected from in vitro intrinsic clearance data.
Abstract: A novel human organic transporter, OATP2, has been identified that transports taurocholic acid, the adrenal androgen dehydroepiandrosterone sulfate, and thyroid hormone, as well as the hydroxymethylglutaryl-CoA reductase inhibitor, pravastatin. OATP2 is expressed exclusively in liver in contrast to all other known transporter subtypes that are found in both hepatic and nonhepatic tissues. OATP2 is considerably diverged from other family members, sharing only 42% sequence identity with the four other subtypes. Furthermore, unlike other subtypes, OATP2 did not transport digoxin or aldosterone. The rat isoform oatp1 was also shown to transport pravastatin, whereas other members of the OATP family, i.e. rat oatp2, human OATP, and the prostaglandin transporter, did not. Cis-inhibition studies indicate that both OATP2 and roatp1 also transport other statins including lovastatin, simvastatin, and atorvastatin. In summary, OATP2 is a novel organic anion transport protein that has overlapping but not identical substrate specificities with each of the other subtypes and, with its liver-specific expression, represents a functionally distinct OATP isoform. Furthermore, the identification of oatp1 and OATP2 as pravastatin transporters suggests that they are responsible for the hepatic uptake of this liver-specific hydroxymethylglutaryl-CoA reductase inhibitor in rat and man.
Abstract: Pravastatin, one of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) widely used in the management of hypercholesterolaemia, has unique pharmacokinetic characteristics among the members of this class. Many in vivo and in vitro human and animal studies suggest that active transport mechanisms are involved in the pharmacokinetics of pravastatin. The oral bioavailability of pravastatin is low because of incomplete absorption and a first-pass effect. The drug is rapidly absorbed from the upper part of the small intestine, probably via proton-coupled carrier-mediated transport, and then taken up by the liver by a sodium-independent bile acid transporter. About half of the pravastatin that reaches the liver via the portal vein is extracted by the liver, and this hepatic extraction is mainly attributed to biliary excretion which is performed by a primary active transport mechanism. The major metabolites are produced by chemical degradation in the stomach rather than by cytochrome P450-dependent metabolism in the liver. The intact drug and its metabolites are cleared through both hepatic and renal routes, and tubular secretion is a predominant mechanism in renal excretion. The dual routes of pravastatin elimination reduce the need for dosage adjustment if the function of either the liver or kidney is impaired, and also reduce the possibility of drug interactions compared with other statins. which are largely eliminated by metabolism. The lower protein binding than other statins weakens the tendency for displacement of highly protein-bound drugs. Although all statins show a hepatoselective disposition, the mechanism for pravastatin is different from that of the others. There is high uptake of pravastatin by the liver via an active transport mechanism, but not by other tissues because of its hydrophilicity, whereas the disposition characteristics of other statins result from high hepatic extraction because of high lipophilicity. These pharmacokinetic properties of pravastatin may be the result of the drug being given in the pharmacologically active open hydroxy acid form and the fact that its hydrophilicity is markedly higher than that of other statins. The nature of the pravastatin transporters, particularly in humans, remains unknown at present. Further mechanistic studies are required to establish the pharmacokinetic-pharmacodynamic relationships of pravastatin and to provide the optimal therapeutic efficacy for various types of patients with hypercholesterolaemia.
Abstract: Involvement of LST-1 (a human liver-specific transporter, also called OATP2) as the major transporter in the uptake of pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, by human liver was demonstrated. The hepatic uptake of pravastatin evaluated using human hepatocytes was Na(+)-independent and reached saturation with a Michaelis constant (K(m)) of 11.5 +/- 2.2 microM. The uptake of pravastatin was temperature-dependent and was inhibited by estradiol-17beta-D-glucuronide, taurocholic acid, bromosulfophthalein, and simvastatin acid, but not by p-aminohippurate. Estradiol-17beta-D-glucuronide competitively inhibited pravastatin uptake with an inhibition constant comparable to the K(m) value for estradiol-17beta-D-glucuronide transport, indicating that a common transporter mediates the transport of pravastatin and estradiol-17beta-D-glucuronide in human hepatocytes. The results obtained with human hepatocytes agreed with those obtained with LST-1 expressing Xenopus oocytes. Oocytes microinjected with human liver polyadenylated mRNA showed Na(+)-independent uptake of pravastatin and estradiol-17beta-D-glucuronide. A simultaneous injection of LST-1 antisense oligonucleotides completely abolished this uptake. Expression of LST-1 was immunohistochemically demonstrated in the human hepatocytes, but not in Hep G2 cells, which showed very low uptake of pravastatin. Therefore, LST-1 was regarded as a key molecule for pravastatin in liver-specific inhibition of cholesterol synthesis, making pravastatin accessible to the target enzyme, which would otherwise not be inhibited by this hydrophilic drug.
Abstract: Human organic anion transporting polypeptide 2 (OATP2/SLC21A6) and multidrug resistance-associated protein 2 (MRP2/ABCC2) play important roles in the vectorial transport of organic anions across hepatocytes. In the present study, we have established a double-transfected Madin-Darby canine kidney (MDCK II) cell monolayer, which expresses both OATP2 and MRP2 on basal and apical membranes, respectively. The basal-to-apical transport of 17 beta estradiol 17 beta-d-glucuronide (E(2)17 beta G), pravastatin, and leukotriene C(4) (LTC(4)), which are substrates of OATP2 and MRP2, was significantly higher than that in the opposite direction in the double-transfected cells. Such vectorial transport was also observed for taurolithocholate sulfate, which is transported by rat oatp1 and Mrp2. The K(m) values of E(2)17 beta G and pravastatin for the basal-to-apical flux were 27.9 and 24.3 microm, respectively, which were comparable with those reported for OATP2. Moreover, the MRP2-mediated export of E(2)17 beta G across the apical membrane was not saturated. In contrast, basal-to-apical transport of estrone-3-sulfate and dehydroepiandrosterone sulfate, which are significantly transported by OATP2, but not by MRP2, was not stimulated by MRP2 expression. The double-transfected MDCK II monolayer expressing both OATP2 and MRP2 may be used to analyze the hepatic vectorial transport of organic anions and to screen the transport profiles of new drug candidates.
Abstract: The pH-sensitive activity of human organic anion transporting polypeptide OATP-B, which is expressed at the apical membrane of human small intestinal epithelial cells, was functionally characterized. When initial uptake of estrone-3-sulfate, a typical substrate of OATP, was studied kinetically, we observed an increase in V(max) with decrease of pH from 7.4 to 5.0, whereas the change in K(m) was negligible. OATP-B-mediated uptake of estrone-3-sulfate was independent of sodium, chloride, bicarbonate, or glutathione, whereas the proton ionophore carbonylcyanide p-trifluoromethoxyphenylhydrazone exhibited a pH-dependent inhibitory effect, suggesting that a proton gradient is a driving force for OATP-B. When OATP-B was expressed in human embryonic kidney 293 cells, uptake activities for anionic compounds showed various kinds of pH sensitivity. Dehydroepiandrosterone-sulfate, estrone-3-sulfate, and fexofenadine were transported by OATP-B at both neutral and acidic pH, whereas estradiol-17beta-glucuronide, acetic acid, and lactic acid were not transported at all. Transport of taurocholic acid and pravastatin by OATP-B was observed only at acidic pH, demonstrating a pH-sensitive substrate specificity of OATP-B. Because the physiological pH close to the surface of intestinal epithelial cells is acidic, the roles of OATP-B in the small intestine might be different from those in other tissues, such as liver basolateral membrane. Although the driving force for OATP-B has not been fully established, the clarification of factors, such as pH, that affect the OATP-B-activity is essential for an understanding of the physiological and pharmacological relevance of the transporter in the small intestine.
Abstract: BACKGROUND: To date, the uptake of drugs into the human heart by transport proteins is poorly understood. A candidate protein is the organic cation transporter novel type 2 (OCTN2) (SLC22A5), physiologically acting as a sodium-dependent transport protein for carnitine. We investigated expression and localization of OCTN2 in the human heart, uptake of drugs by OCTN2, and functional coupling of OCTN2 with the eliminating ATP-binding cassette (ABC) transporter ABCB1 (P-glycoprotein). METHODS AND RESULTS: Messenger RNA levels of OCTN2 and ABCB1 were analyzed in heart samples by quantitative polymerase chain reaction. OCTN2 was expressed in all auricular samples that showed a pronounced interindividual variability (35 to 1352 copies per 20 ng of RNA). Although a single-nucleotide polymorphism in OCTN2 (G/C at position -207 of the promoter) had no influence on expression, administration of beta-blockers resulted in significantly increased expression. Localization of OCTN2 by in situ hybridization, laser microdissection, and immunofluorescence microscopy revealed expression of OCTN2 mainly in endothelial cells. For functional studies, OCTN2 was expressed in Madin-Darby canine kidney (MDCKII) cells. Using this system, verapamil, spironolactone, and mildronate were characterized both as inhibitors (EC50=25, 26, and 21 micromol/L, respectively) and as substrates. Like OCTN2, ABCB1 was expressed preferentially in endothelial cells. A significant correlation of OCTN2 and ABCB1 expression in the human heart was observed, which suggests functional coupling. Therefore, the interaction of OCTN2 with ABCB1 was tested with double transfectants. This approach resulted in a significantly higher transcellular transport of verapamil, a substrate for both OCTN2 and ABCB1. CONCLUSIONS: OCTN2 is expressed in the human heart and can be modulated by drug administration. Moreover, OCTN2 can contribute to the cardiac uptake of cardiovascular drugs.
Abstract: Understanding the mechanisms of drug interactions with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has become increasingly important because of the potential for serious adverse effects, most notably myopathy. Most of the evidence supports the role of cytochrome P450 (CYP) isoenzymes in many of these drug interactions. However, P-glycoprotein (P-gp), an efflux protein located in the gastrointestinal tract, placenta, kidneys, brain, and liver, may also play a role. Results of several studies with in vitro models have shown that lovastatin, simvastatin, and atorvastatin are inhibitors for P-gp and may be substrates for this transporter as well. Pravastatin and fluvastatin consistently demonstrate no significant inhibition of P-gp. Drug interaction studies involving statins and digoxin support a role for P-gp. Many additional drugs such as diltiazem, verapamil, itraconazole, ketoconazole, and cyclosporine, as well as dietary supplements such as St. John's wort and grapefruit juice, interact with statins and are modulators of both CYP3A4 and P-gp. However, the role of P-gp in these specific drug interactions remains unclear.
Abstract: We hypothesized that CYP3A5 genotype contributes to the interindividual variability in verapamil response. Healthy subjects (n=26) with predetermined CYP3A5 genotypes were categorized as expressers (at least one CYP3A5(*)1 allele) and nonexpressers (subjects without a CYP3A5(*)1 allele). Verapamil pharmacokinetics and pharmacodynamics were determined after 7 days of dosing with 240 mg daily. There was a significantly higher oral clearance of R-verapamil (165.1+/-86.4 versus 91.2+/-36.5 l/h; P=0.009) and S-verapamil (919.4+/-517.4 versus 460.2+/-239.7 l/h; P=0.01) in CYP3A5 expressers compared to nonexpressers. Consequently, CYP3A5 expressers had significantly less PR-interval prolongation (19.5+/-12.3 versus 44.0+/-19.4 ms; P=0.0004), and had higher diastolic blood pressure (69.2+/-7.5 versus 61.6+/-5.1 mm Hg; P=0.036) than CYP3A5 nonexpressers after 7 days dosing with verapamil. CYP3A5 expressers display a greater steady-state oral clearance of verapamil and may therefore experience diminished pharmacological effect of verapamil due to a greater steady state oral clearance.
Abstract: AIM: It has been reported that verapamil and atorvastatin are inhibitors of both P-glycoprotein (P-gp) and microsomal cytochrome P450 (CYP) 3A4, and verapamil is a substrate of both P-gp and CYP3A4. Thus, it could be expected that atorvastatin would alter the absorption and metabolism of verapamil. METHODS: The pharmacokinetic parameters of verapamil and one of its metabolites, norverapamil, were compared after oral administration of verapamil (60 mg) in the presence or absence of oral atorvastatin (40 mg) in 12 healthy volunteers. RESULTS: Pharmacokinetics of verapamil were significantly altered by the coadministration of atorvastatin compared with those of without atorvastatin. For example, the total area under the plasma-concentration time curve to the last measured time, 24 h, in plasma (AUC(0-24) (h)) of verapamil increased significantly by 42.8%. Thus, the relative bioavailability increased by the same magnitude with atorvastatin. Although the AUC(0-24) (h) of norverapamil was not significantly different between two groups of humans, the AUC(0-24) (h, norverapamil)/ AUC(0-24) (h, verapamil) ratio was significantly reduced (27.5% decrease) with atorvastatin. CONCLUSION: The above data suggest that atorvastatin could inhibit the absorption of verapamil via inhibition of P-gp and/or the metabolism of verapamil by CYP3A4 in humans.
Abstract: HMG-CoA reductase inhibitors (statins) dose-dependently lower both the level of low-density lipoprotein cholesterol and risk of cardiovascular disease. In 2004, the UK approved a low-dose over-the-counter (OTC) simvastatin, but the US has rejected applications for non-prescription preparations of statins. The pharmacokinetics and interaction potentials of the possible OTC candidate statins simvastatin, lovastatin, fluvastatin and pravastatin are clearly different. Simvastatin and lovastatin are mainly metabolized by cytochrome P450 (CYP) 3A, fluvastatin is metabolized by CYP2C9, and pravastatin is excreted largely unchanged. Several cell membrane transporters can influence the disposition of statins, e.g. the organic anion transporting polypeptide (OATP) 1B1 enhances their hepatic uptake. The c.521T>C (p.Val174Ala) genetic polymorphism of SLCO1B1 (encoding OATP1B1) considerably increases the plasma concentrations of simvastatin acid and moderately increases those of pravastatin but seems to have no significant effect on fluvastatin. Strong inhibitors of CYP3A (itraconazole, ritonavir) greatly (up to 20-fold) increase plasma concentrations of simvastatin, lovastatin and their active acid forms, thus enhancing the risk of myotoxicity. Weak or moderately potent CYP3A inhibitors such as verapamil, diltiazem and grapefruit juice can be used cautiously with low doses of simvastatin or lovastatin, but their concomitant use needs medical supervision. Potent inducers of CYP3A can greatly decrease plasma concentrations of simvastatin and simvastatin acid, and probably those of lovastatin and lovastatin acid. Although fluvastatin is metabolized by CYP2C9, its concentrations are changed less than 2-fold by inhibitors or inducers of CYP2C9. Pravastatin plasma concentrations are not significantly affected by any CYP inhibition and only slightly affected by inducers. Ciclosporin inhibits CYP3A, P-glycoprotein and OATP1B1. Gemfibrozil and its glucuronide inhibit CYP2C8 and OATP1B1. Ciclosporin and gemfibrozil increase plasma concentrations of statins and the risk of their myotoxicity, but fluvastatin seems to carry a smaller risk than other statins. Inhibitors of OATP1B1 may decrease the benefit-risk ratio of simvastatin, lovastatin and pravastatin by interfering with their (active acid forms) entry into hepatocytes. Understanding the differences in the pharmacokinetics and interaction potential of various statins helps in their selection for possible non-prescription status. On the pharmacokinetic basis, fluvastatin and pravastatin can be better choices than simvastatin or lovastatin for an OTC statin.
Abstract: BACKGROUND: Lovastatin is an inhibitor of P-glycoprotein (P-gp) and is metabolized by the cytochrome P450 (CYP) 3A4 isoenzyme. Verapamil is a substrate of both P-gp and CYP3A4. It is therefore likely that lovastatin can alter the absorption and metabolism of verapamil. METHODS: The pharmacokinetic parameters of verapamil and one of its metabolites, norverapamil, were compared in 14 healthy male Korean volunteers (age range 22-28 years) who had been administered verapamil (60 mg) orally in the presence or absence of oral lovastatin (20 mg). The design of the experiment was a standard 2 x 2 crossover model in random order. RESULTS: The pharmacokinetic parameters of verapamil were significantly altered by the co-administration of lovastatin compared to the control. The area under the plasma concentration-time curve (AUC (0-infinity)) and the peak plasma concentration of verapamil were significantly increased by 62.8 and 32.1%, respectively. Consequently, the relative bioavailability of verapamil was also significantly increased (by 76.5%). The (AUC (0-infinity)) of norverapamil and the terminal half-life of verapamil did not significantly changed with lovastatin coadministration. The metabolite-parent ratio was significantly reduced (29.2%) in the presence of lovastatin. CONCLUSION: Lovastatin increased the absorption of verapamil by inhibiting P-gp and inhibited the first-pass metabolism of verapamil by inhibiting CYP3A4 in the intestine and/or liver in humans.
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.
Abstract: BACKGROUND: The most common acquired cause of Long QT syndrome (LQTS) is drug induced QT interval prolongation. It is an electrophysiological entity, which is characterized by an extended duration of the ventricular repolarization. Reflected as a prolonged QT interval in a surface ECG, this syndrome increases the risk for polymorphic ventricular tachycardia (Torsade de Pointes) and sudden death. METHOD: Bibliographic databases as MEDLINE and EMBASE, reports and drug alerts from several regulatory agencies (FDA, EMEA, ANMAT) and drug safety guides (ICH S7B, ICH E14) were consulted to prepare this article. The keywords used were: polymorphic ventricular tachycardia, adverse drug events, prolonged QT, arrhythmias, intensive care unit and Torsade de Pointes. Such research involved materials produced up to December 2017. RESULTS: Because of their mechanism of action, antiarrhythmic drugs such as amiodarone, sotalol, quinidine, procainamide, verapamil and diltiazem are associated to the prolongation of the QTc interval. For this reason, they require constant monitoring when administered. Other noncardiovascular drugs that are widely used in the Intensive Care Unit (ICU), such as ondansetron, macrolide and fluoroquinolone antibiotics, typical and atypical antipsychotics agents such as haloperidol, thioridazine, and sertindole are also frequently associated with the prolongation of the QTc interval. As a consequence, critical patients should be closely followed and evaluated. CONCLUSION: ICU patients are particularly prone to experience a QTc interval prolongation mainly for two reasons. In the first place, they are exposed to certain drugs that can prolong the repolarization phase, either by their mechanism of action or through the interaction with other drugs. In the second place, the risk factors for TdP are prevalent clinical conditions among critically ill patients. As a consequence, the attending physician is expected to perform preventive monitoring and ECG checks to control the QTc interval.
Abstract: Amiodarone is one of the most commonly used antiarrhythmic drugs. Despite its well-known side effects, amiodarone is considered to be a relatively safe drug, especially in short-term usage to prevent life-threatening ventricular arrhythmias. Our case demonstrates an instance where short-term usage can yield drug side effect.