Fjc200640 1.8

Experimental Hyperlipidemia Causes an Increase in the Dalia A. Hamdy, MSc and Dion R. Brocks, PhD be caused by several factors such as genetic makeup or Abstract: To assess the influence of hyperlipidemia (HL) on secondarily to other factors including diet and lifestyle habits amiodarone (AM) effect in the heart, rats were pretreated with either 1 and diseases or drugs.1–3 Plasma lipoproteins, which are the g/kg poloxamer 407 (to induce HL) or saline intraperitoneally. At packages via which lipid movement is accomplished through approximately 36 hours afterward, rats were given AM HCl (25, 50, the body, can be classified based on their density and content and 100 mgÁkg21Ád21) or saline intravenously through implanted of lipid, protein, and apoprotein3 into chylomicrons, very low venous cannulas for 5 days. Under anesthesia, electrocardiogram density lipoproteins (VLDL), intermediate-density lipopro- (ECG) was recorded using subcutaneous electrodes and blood teins (IDL), low-density lipoproteins (LDL), and high-density samples were withdrawn at baseline and 12 hours after the first, lipoproteins. Elevated plasma LDL is a known direct middle, and last doses. At the end of the study, heart tissues were contributor to an increased risk of atherosclerosis and coronary collected. Specimens were analyzed for AM and desethylamiodarone.
heart diseases.4–7 Evidence has also emerged that elevated HL by itself did not alter the ECG. Compared with baseline, the end plasma lipoprotein could influence the pharmacokinetic, phar- of study prolongation of QTc and PR intervals were significantly macodynamic, and toxicodynamic properties of lipoprotein- (P , 0.05) higher in all AM-treated HL rats. AM plasma and heart bound drugs.8–11 In addition to a change in plasma-unbound concentrations in HL rats after the last dose were significantly (P , fraction, tissue lipoprotein receptor mediated uptake of lipo- 0.05) higher than in normolipidemic rats. Similar to AM, in HL rats, proteins and encapsulated drug also potentially mediated drug plasma desethylamiodarone after the last dose was significantly higher than in normolipidemic rats. The cholesterol to triglyceride One drug that has emerged to prominence in the plasma ratio was linearly related to QT interval and plasma and heart treatment of cardiac arrhythmias is the iodinated class III AM concentrations. HL increased the ECG effects of AM by antiarrhythmic drug, amiodarone (AM).12,13 In addition to being a blocker of potassium channels, AM also possesses Key Words: amiodarone, antiarrhythmics, biodistribution, hyperlip- weak sodium channel–blocking activity, noncompetitive idemia, pharmacokinetics/pharmacodynamics inhibition of a- and b-adrenergic receptors, and vagolyticand calcium channel–blocking effects.14,15 This complex range (J Cardiovasc Pharmacol TM 2009;00:1–8) of receptor inhibition results in prolongation of severalparameters measurable in the electrocardiogram (ECG),including the QRS complex and RR, PR, and QTc intervals.
Owing to its proven record of efficacy, AM is commonly used The worldwide increases in obesity rates are associated as first-line therapy for the treatment of patients with with an increase in the prevalence of hyperlipidemia (HL) and the risk of cardiovascular disease.1 HL, which is characterized The highly lipophilic nature of AM contributes to its by abnormally high concentrations of plasma lipoproteins, can complex pharmacokinetic properties.14 It is extensively boundto plasma proteins in rats and humans, and a significantamount of the binding is to lipoproteins.18 AM possesses Received for publication September 23, 2008; accepted October 30, 2008.
erratic absorption (35%–65%) with low and unpredictable oral From the Faculty of Pharmacy and Pharmaceutical Sciences, University of bioavailability.19 Its extensive tissue uptake results in a large Supported by Canadian Institutes of Health Research Grant Number MOP volume of distribution and long terminal phase half-life (t½).12,20,21 The drug also possesses a low to moderate hepatic Presented in part at the Canadian Society for Pharmaceutical Sciences extraction ratio and is extensively metabolized.12 AM is well Meeting, May 30–June 2, 2008, Montreal, Quebec, Canada. D.A.H. was taken up by heart tissues, and a positive cardiac concentration the recipient of the Biovail Contract Research Award of Excellence for thepresentation.
versus effect relationship is present for its changes in the D.A.H. is a recipient of a studentship from the government of Egypt.
Reprints: Dion R. Brocks, PhD, Associate Professor, Faculty of Pharmacy and HL rats are known to attain higher AM plasma Pharmaceutical Sciences, 3118 Dentistry–Pharmacy Centre, University of concentrations, lower clearance (CL), volume of distribution Alberta, Edmonton, Alberta, Canada T6G 2N8 (e-mail: dbrocks@ d), and unbound fraction than normolipidemic (NL) rats.12 It Copyright Ó 2009 by Lippincott Williams & Wilkins is the unbound drug concentrations in plasma that are normally J Cardiovasc Pharmacol ä  Volume 00, Number 0, Month 2009 J Cardiovasc Pharmacol ä  Volume 00, Number 0, Month 2009 believed to be the only form of drug capable of transversing heparin in 0.9% saline. After surgery, the animals were cell membranes, thereby facilitating pharmacological action.
transferred to regular holding cages and allowed for free access However, in HL rats, it was apparent that AM uptake by some to water. The next morning, the rats were transferred to plastic tissues, including heart, seemed to be greater than expected metabolic cages and dosing was performed.
based on the calculated unbound drug concentrations.22 Thissupported the concept that lipoprotein-bound drug can be selectively taken up by lipoprotein receptors in the heart.
Given that HL caused higher heart concentrations of At the dose levels described above, AM or an equivalent AM after single doses, it would be expected to cause increases volume of saline vehicle was injected every 12 hours for 5 in its pharmacological effect on the heart. However, AM is days, for a total of 10 doses starting approximately 36 hours given as repeated doses, and what might happen to drug heart after the first IP doses of P407 or saline. The AM-injectable uptake and effect under this situation is unclear. It has been solution was diluted using saline for injection to provide a final noted before that the use of single-dose data with classical concentration of 12.5 mg/mL. Each IV dose was injected over pharmacokinetic models can fail to adequately describe the 60 seconds via the jugular vein cannula, immediately followed time course of plasma AM concentration during long-term by injection of 0.5 mL of 0.9% NaCl for injection and 0.15 mL treatment.25 To further explore the possible pharmacological of cannula lock solution consisting of 25% heparin 1000 outcome of this altered drug uptake in the presence of HL, this U/mL, 55% polyethylene glycol 400, and 20% cefazolin 100 study was devised using rats in which elevation in lipoproteins mg/mL. Because of the known pharmacokinetics and duration was experimentally induced concomitantly with repeated dose of effect of P407,26 the HL state was maintained over the exposure to AM intravenously (IV), over a range of doses.
course of the study by injecting the animals with a second doseof P407, just after the fifth dose of AM was administered.
The NL rats were injected equivalent volumes of saline IP atthe same times.
Under light isoflurane anesthesia, 12-second ECG strips AM HCL, ethopropazine HCL, and poloxamer 407 were recorded using stainless steel subdermal needle electro- (P407) were obtained from Sigma (St. Louis, MO). Desethy- des, P55 general purpose AC preamplifier and PolyVIEW data lamiodarone (DEA) was obtained as a kind gift from Wyeth acquisition and analysis system (Grass Instrument Division, Ayerst (Research Monmouth Junction, NJ). Heparin sodium Astro-Med, Inc, West Warwick, RI). The ECG recordings were injection (Leo Pharma, Thornhill, Ontario, Canada), cefazolin collected at baseline conditions (at the time of the first (Novopharm, Toronto, Ontario, Canada), and AM HCl 50 prestudy dose of P407) and at 12 hours after doses 1, 5, and 10 mg/mL for injection (Sandoz, Dorval, Quebec, Canada) were during the AM postdistributive phase.12 The PR, RR, and QT each purchased from the University of Alberta Hospitals.
intervals, the latter of which was measured from the Q wavedeflection to the time where the isoelectric point was reached after the T wave, were recorded. The QT interval was This study was performed using a total of 56 male normalized to the heart rate (QTc) using Fridericia [QTc = Sprague–Dawley rats (Charles River, Montreal, Quebec) with QT/(RR)1/3] and Bazett (QTc = QT/RR1/2) formulas.27,28 After body weight ranging from 250 to 350 g. The study protocol collection of all the ECG strips, a random code value was was approved by the University of Alberta Health Sciences assigned to each strip before measurement of ECG parameters.
Animal Policy and Welfare Committee. All rats were housed in This ensured that the ECGs were evaluated in a blinded temperature-controlled rooms with 12-hour light per day. The fashion by the assessor, who did not know which treatment animals were fed a standard rodent chow containing 4.5% fat was given or the time of ECG obtainment of each (Lab Diet 5001; PMI nutrition LLC, Brentwood, CA). Free access to food and water was permitted throughout the In conjunction with the ECG data collection, blood samples (0.15–0.2 mL) were withdrawn from the tail vein The rats were allocated into several groups, stratified by immediately after measurement of the ECG at baseline and lipoprotein status and AM dosage. The protocol included after doses 1 and 5. Cardiac puncture was used to withdraw saline-treated control rats, and rats were given discrete AM blood at the end of the study. The plasma was separated from dose levels of 25, 50, and 100 mgÁkg21Ád21. For each of these blood by centrifugation for 5 minutes at 2500g and used for groups, there was a matching NL group and HL group. Each measurement of AM and DEA plasma concentrations. The drug-free control group included 4 rats, whereas each of the blood withdrawn at the end of the study was also used to AM-dosed groups for NL and HL status contained 8 rats.
measure plasma lipid concentrations. After blood withdrawal The HL-induced rats were injected 1 g/kg intraperitoneal by cardiac puncture, hearts were also harvested followed by (IP) doses of P407 (0.13 g/mL solution in normal saline). To blotting with tissue paper to remove excess blood. All plasma ensure the proper injection of P407, the animals were lightly and tissue specimens were stored at 230°C until assayed.
anesthetized using isoflurane and then allowed to recover. Atapproximately 18 hours afterward, the right jugular veins of all rats were cannulated with Silastic tubing (Dow Corning, A previously reported validated method was used for Midland, MI) under isoflurane/O2 anesthesia, administered by the analysis of AM and DEA in plasma and heart tissues.29 anesthetic machine. The cannulas were filled with 100 U/mL For the assay of drug and metabolite, corresponding blank J Cardiovasc Pharmacol ä  Volume 00, Number 0, Month 2009 drug-free plasma and homogenized heart tissues from HL and QTc intervals in HL than in NL rats, and in all dose groups, NL rats spiked with known amounts of AM and DEA were significant differences between HL and NL were apparent after used for the construction of standard curves.
the last dose (Fig. 1; Table 1). The QTc interval prolongations Total cholesterol (CHOL) and triglyceride (TG) con- after the last dose in HL rats versus NL rats were 19.9% 6 centrations were determined using enzymatic CHOL and TG 8.5% and 8.8% 6 6.3% for 25 mgÁkg21Ád21, 23.9% 6 7.1% assay kits according to the manufacturer’s directions.
and 9.2% 6 3.3% for 50 mgÁkg21Ád21, and 86.8% 6 18.2%and 51.3% 6 22.0% for the 100 mgÁkg21Ád21 treated rats, respectively. Similarly, after the last dose, all AM-treated HL The accumulation factors for AM in plasma were rats showed significant (P , 0.05) prolongations in PR determined as the quotient of the last measured concentration interval compared with equivalently treated NL rats (Table 1), to that 12 hours after the first dose. Data were reported as where the respective increases in PR interval for the HL and mean 6 SD unless otherwise stated. The comparisons of NL rats were 12.4% 6 3.9% versus 5.54% 6 3.9% after 25 means were done using 1-way analysis of variance followed by mgÁkg21Ád21, 14.5% 6 9.0% versus 5.80% 6 3.3% after 50 Duncan multiple range post hoc or Student unpaired or paired mgÁkg21Ád21, and 23.1% 6 4.2% versus 18.6% 6 4.1% after t tests as appropriate (Microsoft Excel 2003; Microsoft, 100 mgÁkg21Ád21. There were moderate yet significant, Redmond, WA, and SPSS 16.0; SPSS Inc, Chicago, IL). The positive, linear correlations between the percent changes in level of significance was set at a = 0.05.
QTc and PR intervals in both NL (r2 = 0.381) and HL (r2 =0.346) rats. In evaluating the RR interval, similar magnitudes ofprolongation were present in both the NL and HL rats at each dose level. Only for the 50 mgÁkg21Ád21 treated HL rats was As expected,13 P407 caused increases in both TG and there a significant difference noted from NL in the RR (Table 1).
total CHOL levels in rat plasma. Compared with NL rats, the The DEA concentrations were consistently lower than HL rats showed considerable increases of 13.7-fold and 33.8- those of AM in plasma and heart, in both NL and HL rats fold in the total CHOL and TG levels, respectively, by the end (Table 1). Significant (P , 0.001) and strong linear correlations were found between DEA and AM present in The HL condition by itself had no effect on QT, QTc, plasma (r2 = 0.794 and 0.950, respectively) and heart (r2 = PR, or RR intervals in saline control rats (Table 1). The 0.913 for both NL and HL) of both NL and HL rats. In line increase in RR, PR, and QTc intervals from baseline, with previous single-dose studies,12,22 throughout the study, all respectively, was 20.42% 6 8.75%, 1.13% 6 5.64%, and AM-treated HL rats had substantially higher AM plasma 0.95% 6 1.47% in NL saline control rats versus 2.29% 6 concentrations than equivalently treated NL rats (Table 1). In 3.15%, 2.34% 6 3.29%, and 4.36% 6 5.74% in HL. AM was comparison, DEA plasma concentrations of AM-treated HL found to prolong QT, QTc, PR, and RR intervals in both NL rats were only significantly (P , 0.05) different from the and HL rats (Table 1). In general, there were longer QT and equivalently treated NL rat groups, 12 hours after the last dose TABLE 1. The ECG Parameters, AM and DEA Concentrations in Plasma and Heart, and CHOL and TG Content of NL and HL SalineControl and AM-treated Rats 12 Hours After the Last Dose 0.034 6 0.008 0.095 6 0.043* 0.107 6 0.065 0.296 6 0.124* 0.314 6 0.096 2.22 6 0.868* J Cardiovasc Pharmacol ä  Volume 00, Number 0, Month 2009 FIGURE 1. Percent change in QTcinterval (mean 6 SD) in NL and HLrats after IV doses of 0, 25, 50, and100 mgÁkg21Ád21 AM HCl on days 1,3, and 6 of the study. *Significantdifference between HL and NL rats(P , 0.05).
(Table 1). At the end of the study, heart AM concentrations differential in the slope (approximately 10-fold higher for NL) were significantly higher (.1.7-fold) in AM-treated HL rat between the NL and HL animals. Similarly, there was a strong groups than likewise treated NL rat groups (P , 0.05; Fig. 2).
linear correlation between AM heart concentrations and The heart concentrations of DEA in all groups showed a trend change in QTc, although here the slopes were similar (Fig.
(.1.3-fold) toward increases in HL rats compared with NL rats, 3). The relationships between total AM heart uptake and total although the values were variable, and statistical differences AM plasma concentration for both NL and HL rat groups were only detected between the 100 mgÁkg21Ád21 AM-treated yielded strong correlations although with different slopes HL and NL rats (Table 1). A disproportionate increase in AM (NL = 9.6; HL = 1.3, Fig. 4). These slope values closely plasma and heart concentrations was noted 12 hours after the matched those of the heart to plasma concentration ratios (Kp) last dose in NL and HL rat groups upon increasing the daily previously observed for AM when given as single doses to NL dose from 50 to 100 mgÁkg21Ád21. Thus a 2-fold increase in (8.7) and HL (2.1).22 Strong positive and significant linear the dose resulted in .4-fold increase in AM plasma and heart correlations were noted in the plasma CHOL:TG ratios versus trough concentrations in both NL and HL rats (Fig. 2; Table 1).
the QT interval, plasma AM, and heart AM concentrations The same dose-dependent nonlinear pattern was demonstrated (Fig. 5), for both NL and HL rats. The slopes of the relationships, however, were much higher for the HL rats.
For the NL rats, the accumulation factors for mean plasma concentrations, respectively, were 1.96 6 0.58, 1.59 60.155, and 4.87 6 1.60 for the 25, 50, and 100 mgÁkg21Ád21 doses. The corresponding accumulation factors for HL rats The HL state is a precursor to cardiovascular disease were 8.08 6 11.9, 15.0 6 17.6, and 27.5 6 38.4, respectively.
and as such is likely to be present in patients receiving AM.
In terms of ranking, the accumulation factor of the highest To induce HL here, P407 was used; its IP administration is dose of NL rats was significantly higher than that of the lower known to cause a profound but reversible rise in circulating doses in NL rats. There were no differences noted between lipoprotein, particularly those of the very low density cate- accumulation factors of the HL rats.
gory.30 Although lipoprotein concentrations are greatly in- There was a strong correlation noted between AM creased, it does so with no apparent toxicity, and additionally, plasma concentrations and change in QTc interval, in both NL P407 provides one of the few rodent models of HL in which, and HL rat groups (Fig. 3). However, there was a large J Cardiovasc Pharmacol ä  Volume 00, Number 0, Month 2009 prolongation in the QTc, RR, and PR intervals of the ECG.
Some strong linear correlations were observed between AMheart concentrations and QTc interval prolongation in both NLand HL rats with very similar slopes, indicating similar effectsat the level of the heart (Fig. 3). However, although therelationship between AM total (bound + unbound) plasmaconcentrations and QTc interval prolongation was linear inboth groups, the slope in NL rats was 10-fold higher than HLrats, suggesting heterogeneity in the heart uptake of the drugbetween the 2 groups (Fig. 3). Because it is commonlybelieved that only the unbound drug is capable of traversingthe cell membrane and exerting the pharmacological activity,and because the drug had the same concentration versus effectrelationship at the level of the heart (Fig. 3), the slopes ofunbound concentration versus heart uptake should match. Itwas possible to estimate the unbound AM plasma concentra-tions by multiplying previously obtained estimates of theunbound fraction in NL (0.0853%) and HL (0.00345%) plasmaby the total drug (bound + unbound) concentrations.12,22 Indoing so, it was clear that there was a difference in NL and HLslopes of unbound plasma AM concentrations and heart uptake,indicating that an additional factor besides unbound fraction wasinvolved in controlling uptake of AM into the heart (Fig. 4).
It had previously suggested that the cause of the increased heart concentrations of AM in HL rats was at least inpart due to the influence of VLDL receptor–mediated uptakeof drug.22 There are 9 members of the LDL receptor familywhich comprise cell surface receptors that transport a numberof lipoproteins, and lipoprotein-encapsulated drug, into cellsthrough endocytosis.33 The VLDL receptors, which area member of the LDL receptor family, are abundantlyexpressed in fatty acid–active tissues (heart, muscle, andadipose) and macrophages.34 Unlike LDL receptors, in-tracellular lipoproteins do not downregulate VLDL receptor FIGURE 2. AM plasma and heart concentrations (mg/mL) in NL expression.34,35 It has been reported that in HL plasma, there is and HL rats 12 hours after the last AM HCl doses of 25, 50, or a substantial shift of drug and metabolite mostly from the 100 mgÁkg21Ád21. *Significant difference between NL and HL lipoprotein-deficient plasma fractions to the chylomicron and VLDL fractions,36 which is in line with the high level ofVLDL receptor expression in heart.
The positive correlations (Fig. 5) noted between the total induced.31 It has been shown to increase the plasma CHOL:TG ratio and the QT interval, AM plasma, and heart concentrations of several drugs including AM after single concentrations at first glance would seem to contradict the doses,12,22,32 due to increased plasma lipoprotein binding and involvement of VLDL receptors in the heart uptake of AM, reduction in metabolism. In the rat, AM has a moderate hepatic because next to chylomicrons, VLDL possesses the lowest extraction ratio, and as such a decrease in unbound fraction CHOL:TG ratio of all lipoproteins. It must be recognized, should be expected to cause either no change or a decrease in however, that it is not VLDL itself that is taken up by cells the tissue uptake of the drug. However, as was recently through the actions of VLDL-mediated endocytosis but rather reported, in some tissues, HL caused increases in concen- VLDL remnants, also called IDL.37 The IDL particles are the trations, and notably, one of these tissues was the heart.22 This product of the action of lipoprotein lipase, which facilitates the was confirmed here in the present repeated dose study in which loss of TG from the VLDL particles. Further loss of TG from heart AM concentrations were higher in HL rats and where IDL particles causes them to become LDL particles. The ECG changes were in line with the higher tissue concen- VLDL receptors also possess lipolytic activity and further aid in the transformation of VLDL to IDL.34 Therefore, the correla- AM has been classified as a Vaughan-Williams class III tions observed between total CHOL:TG ratio versus QT interval antiarrhythmic agent. Such activity results in increases in atrial and heart concentrations are still consistent with the uptake of and ventricular refractoriness. It also depresses automaticity of AM into VLDL. In plasma, although the AM shift to VLDL is the sinoatrial node, resulting in slowing of the heart rate. The apparently greater than that to LDL fractions in HL plasma, the drug also slows conduction and increases refractoriness of the AM association to LDL is virtually identical in NL and HL atrioventricular node.14 These effects can be visualized by plasma.36 This suggests that the affinity of AM to LDL, with its J Cardiovasc Pharmacol ä  Volume 00, Number 0, Month 2009 FIGURE 3. The correlation betweenpercent increase in QTc interval inNL and HL rats and AM plasma orheart concentrations of all drug-treated rats at the time of heartcollection. Open circles, closed tri-angles, and open squares represent100, 50, and 25 mgÁkg21Ád21 AMdose groups, respectively.
higher CHOL:TG ratio, is greater than to VLDL. Therefore, in thought to be dose dependent.38,39 Similar observations were plasma, which contains higher CHOL:TG ratios, more AM made in human where long-term AM therapy resulted in might be anticipated to be present in the LDL particles, which in turn might lead to a lower AM plasma–unbound fraction and The values of ECG parameters in saline control rats came increased total (bound + unbound) AM concentrations in in accordance with those previously published (Table 1).27 plasma, as was seen in these HL rats (Fig. 5, upper panels).
As anticipated, AM treatment resulted in PR, RR, and QTc It was apparent that the total CHOL:TG ratio was similar interval prolongations in both NL and HL rats. However, HL- between the 25 and 50 mgÁkg21Ád21 doses but higher with the treated rats showed significantly more prominent PR and QTc 100 mgÁkg21Ád21 dose (Fig. 5). This pattern was similar for prolongation than equivalently treated NL rats. This was not each of the NL and HL rats, suggesting that AM by itself may attributed to the HL condition as there was essentially no differ- be affecting the lipid profile. It was previously reported that ence in ECG parameters between NL and HL AM-untreated AM could significantly increase the CHOL and phospholipid rats (Fig. 1; Table 1). Although there was only slight difference levels without altering the TG levels in rat, an increase that was between RR interval prolongation among HL and NL AM- FIGURE 4. The correlation betweenheart and total or unbound plasmaAM concentrations in all drug-trea-ted NL and HL rats.
J Cardiovasc Pharmacol ä  Volume 00, Number 0, Month 2009 FIGURE 5. The correlation betweenplasma total CHOL:TG ratio withplasma AM concentration, heartAM concentration, and QT intervalin NL and HL rats. Open circles,closed triangles, and open squaresrepresent treated rats, QT was still corrected for heart rate and QTc was glomerular changes in kidneys of HL rats than in NL ones.10 In calculated using both Bazett28 and Fridericia27 formulas for contrast, prostaglandin E1 and phenylephrine showed a re- comparison. Whichever measure of QT was used, the pro- duced effect on the blood pressure of atherosclerotic HL longation from baseline was essentially the same and yielded rabbits,11 although it should be noted that the extent of LDL the same comparative statistical results, be it for NL or HL rats.
association of prostaglandin is weak and limited,42,43 and Examples of the effect of HL on the nature of the information regarding the binding of phenylephrine to concentration versus effect relationships have been reported for other drugs. For example, a 31% decrease in nifedipine- Some nonlinearity in the dose versus concentration unbound fraction and a significantly lower area under the data was apparent. The increase in AM plasma and heart unbound plasma concentration–time curve were observed in concentrations was relatively linear between the 25 and P407 HL compared with NL rats. Despite the lower area under 50 mgÁkg21Ád21 dose levels (Fig. 2). However, a greater than the unbound concentration versus time curve, a trend toward linear increase was apparent upon increasing the dose from higher nifedipine-related reduction in mean arterial pressure 50 to 100 mgÁkg21Ád21. Such nonlinear behavior in AM was observed in HL.2 Similarly, the nephrotoxicities of both concentrations with escalating dose has been previously cyclosporine A and amphotericin B, each of which is bound to reported within these dose ranges after single IV doses.44 lipoproteins, were enhanced by HL.10,41 In P407 HL rats given The apparent nonlinearity was accompanied by a similar repeated doses of cyclosporine, microscopic examination of pattern in the relationships between dose and ECG interval stained kidney slices suggested more severe tubular and J Cardiovasc Pharmacol ä  Volume 00, Number 0, Month 2009 22. Shayeganpour A, Korashy H, Patel JP, et al. The impact of experimental hyperlipidemia on the distribution and metabolism of amiodarone in rat.
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