Distribution of amiodarone and its metabolite, desethylamiodarone, in human tissues

The distribution of the antiarrhythmic drug amiodarone and its principal lipophilic metabolite, desethylamiodarone, was determined in postmortem tissues of six patients who received amiodarone therapy (treatment period, 6-189 days; total dose, 4.8-127.0 g). Amiodarone concentration was highest in liver, lung, adipose tissue, and pancreas, followed by kidney, heart (left ventricle), and thyroid gland, and lowest in antemortem plasma. There was no measurable amiodarone in brain (less than 1.0 microgram/g). Desethylamiodarone concentration was highest in liver and lung, followed by pancreas, adipose tissue, kidney, heart, thyroid gland, and brain, and lowest in plasma. For most patients, the desethylamiodarone concentration was higher than the amiodarone concentration in liver, lung, kidney, heart, thyroid gland, and brain, whereas the parent drug concentration was higher than the metabolite concentration in adipose tissue, pancreas, and plasma. Tissue amiodarone and desethylamiodarone concentrations appeared to be related more closely to the total dose of amiodarone than to their respective plasma concentrations. One patient died of apparent amiodarone-induced pulmonary toxicity after an 18-day period of pharmacotherapy. Clinical evidence of pulmonary dysfunction appeared at 15 days after the initiation of amiodarone therapy, and the patient died at 23 days. Histologic assessment of a lung necropsy specimen revealed acute alveolar interstitial damage. This case represents the earliest reported incident of amiodarone-induced pulmonary toxicity.     

Amiodarone inhibits T4 to T3 conversion and alpha-glycerophosphate dehydrogenase and malic enzyme levels in rat liver

Amiodarone has been found to decrease serum T3 by blocking peripheral T4 5'-deiodinase. This reduction in T3 levels may contribute to the effectiveness of this drug in moderating cardiac arrhythmias. To further characterize the effect of amiodarone on thyroid hormone metabolism and biological action, male Sprague-Dawley rats were thyroidectomized and then fed 500 ug T4 or 50 ug T3 and 500 mg amiodarone/kg of powdered diet for 6 to 8 weeks. Hepatic and cardiac levels of T4, T3, alpha-glycerophosphate dehydrogenase (GPD) and malic enzyme (ME) were used as indicators of thyroid hormone availability and action at the cellular level. Conversion of T4 to T3 was measured in liver homogenates. Serum TSH, T4 and T3 were also measured. Amiodarone reduced hepatic GPD and ME in thyroidectomized rats receiving dietary T4. Liver T4 levels were significantly increased by amiodarone and the T3/T4 ratio was reduced (P less than .05). Amiodarone inhibited hepatic T4 to T3 conversion and decreased serum T3. The decreased T3 action at the cellular level, indicated by the reduction in hepatic GPD and ME, is not due to pharmacologic effects of amiodarone since these enzyme levels were not affected by amiodarone in thyroidectomized rats replaced with T3.     

Evidence for an inhibition of thyroid hormone effects during chronic treatment with amiodarone

The effects of chronic amiodarone treatment on several thyroid and cardiac function parameters were studied in 50 euthyroid patients with refractory ventricular arrhythmias, divided in responders and nonresponders according to their sensitivity to the antiarrhythmic action of the drug. No differences in the severity of cardiac disease and blood amiodarone concentrations were found in the two groups. Amiodarone induced a significant inhibition of peripheral T4 monodeiodination, more pronounced in responders compared to nonresponders. On the contrary, only in responsive patients, elevated basal and TRH-stimulated TSH levels were observed (despite serum T3 levels were not different from those in nonresponders) and the indirect indices of cardiac performance, particularly the systolic time intervals, fell in a range usually observed in the hypothyroid states. These findings suggest that amiodarone, besides the well-known inhibition of T4 to T3 conversion, also induces a partial resistance to the thyroid hormones, which is probably involved in the therapeutical effectiveness of the drug.     

Amiodarone antagonizes the effects of T3 at the receptor level: an additional mechanism for its in vivo hypothyroid-like effects

Amiodarone is a diiodinated benzofuran derivative that has some structural similarities to the thyroid hormones and contains two iodine atoms per molecule. It has exhibited hypothyroid-like effects that are thought to be the result of an inhibition of thyroid hormone synthesis due to iodine load, a decrease in the T4 to T3 conversion, and (or) a competitive binding for T3 receptors. The aim of this study was to determine if this third mechanism contributes to the hypothyroid-like effects of amiodarone in vivo. To do so, some characteristic features known to be influenced by hypothyroidism were determined in surgically thyroidectomized rats (n = 48), which received replacement doses of T3 (0.5 and 1.0 microgram.100 g-1.day-1) with or without amiodarone (60 mg.kg-1.day-1). Thyroidectomy produced a hypothyroid state upon which amiodarone had no detectable effects except a negative body weight gain. T3 (0.5 microgram) nearly normalized the thyroid status of the animals, but the concomitant administration of amiodarone induced hypothyroid-like effects suggesting that these effects are dependent on T3. Higher doses of T3 (1.0 microgram) produced hyperthyroid-like effects and attenuated the effects of amiodarone. Unexpectedly, amiodarone decreased T3 plasma concentrations. To determine if the effects of amiodarone were the results of a decrease in T3 plasma and myocardial concentrations or a competition with T3 for its receptors, exogenous T3 pharmacokinetics were studied in thyroidectomized rats receiving T3 (0.5 microgram) with or without amiodarone. The results suggested that amiodarone increased T3 cardiac concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Amiodarone-induced changes in lipid metabolism

Hypothyroidism is a major cause of secondary hypercholesterolemia. Amiodarone treatment alters both the levels of serum lipids and thyroid hormones. We investigated whether the amiodarone-induced changes in lipid metabolism are related to the changes in thyroid hormone levels. Eighteen patients received amiodarone (31 +/- 3 g cumulative dose) for six weeks. Serum triglyceride, total-cholesterol, high density lipoprotein-cholesterol and its subfractions, apolipoproteins B and AI, and plasma post-heparin lipoprotein lipase and hepatic triglyceride lipase activities were determined. Amiodarone treatment caused significant increases in serum total-cholesterol (baseline 4.4 +/- 0.21 (SE), 6 weeks 5.12 +/- 0.26 mmol/l, P less than 0.01), in low density lipoprotein cholesterol (baseline 2.61 +/- 0.26, 6 weeks 3.36 +/- 0.21 mmol/l, P less than 0.05) and in apolipoprotein B (baseline 1.95 +/- 0.15, 6 weeks 2.26 +/- 0.13 mmol/l, P less than 0.01) concentrations. Serum high density lipoprotein and its subfractions, or apolipoprotein AI levels did not change. Plasma post-heparin lipoprotein lipase activity increased (baseline 137 +/- 21, 6 weeks 168 +/- 21 U/ml, P less than 0.01) while hepatic triglyceride lipase did not change. Amiodarone also caused an increase in serum thyroxine (baseline 110 +/- 8, 6 weeks 136 +/- 6 mmol/l, P less than 0.05), although values remained in euthyroid range. In summary, amiodarone therapy increased the concentrations of atherogenic lipoproteins in the serum similar to that seen in hypothyroidism. On the other hand the effect of amiodarone on lipoprotein lipase was opposite to that seen in hypothyroidism. Therefore, amiodarone-induced changes in lipid metabolism cannot be explained solely on the basis of the changes in circulating thyroid hormone levels.     

High-performance liquid chromatographic isolation and fast atom bombardment mass spectrometric identification of Di-N-desethylamiodarone, a new metabolite of amiodarone in the dog

Amiodarone is an antiarrhythmic drug which has received considerable attention in recent years. It has been suggested that the unusual pharmacodynamic characteristics of this drug may be due in part to the influence of active metabolites. Using fast atom bombardment (FAB) mass spectrometry we have identified a new metabolite of amiodarone, the di-N-desethyl analog (DDEA). This metabolite was present in the blood of dogs treated with the parent drug, and showed a greater affinity for myocardium than did the parent drug. The unique features of FAB mass spectrometry over electron impact mass spectrometry was an essential element in facilitating the identification of this new metabolite. Whether or not this metabolite has pharmacologic activity or is responsible for some of the side effects occurring during amiodarone administration is not known.     

Desethylamiodarone interferes with the binding of co-activator GRIP-1 to the beta 1-thyroid hormone receptor

Ligand binding to the thyroid hormone nuclear receptor beta1 (TRbeta(1)) is inhibited by desethylamiodarone (DEA), the major metabolite of the widely used anti-arrhythmic drug amiodarone. Gene expression of thyroid hormone (triiodothyronine, T(3))-regulated genes can therefore be affected by amiodarone due to less ligand binding to the receptor. Previous studies have indicated the possibility of still other explanations for the inhibitory effects of amiodarone on T(3)-dependent gene expression, probably via interference with receptor/co-activator and co-repressor complex. The binding site of DEA is postulated to be on the outside surface of the receptor protein overlapping the regions where co-activator and co-repressor bind. Here we show the effect of a drug metabolite on the interaction of TRbeta(1) with the co-activator GRIP-1 (glucocorticoid receptor interacting protein-1). The T(3)-dependent binding of GRIP-1 to the TRbeta(1) is disrupted by DEA. A DEA dose experiment showed that the drug metabolite acts like an antagonist under 'normal' conditions (at 10(-7) M T(3) and 5x10(-6)-->10(-3) M DEA), but as an agonist under extreme conditions (at 0 and 10(-9) M T(3) and >10(-4) M DEA). To our knowledge, these results show for the first time that a metabolite of a drug which was not devised for this purpose can interfere with nuclear receptor/co-activator interaction.     

Amiodarone N-deethylation in human liver microsomes : Involvement of cytochrome P450 3A enzymes (first report)

Experiments were conducted on three different human liver samples to identify the cytochrome P450 isozyme which is involved in the biotransformation of the class III antiarrhythmic agent, amiodarone, into its major metabolite, desethylamiodarone (DEA). The classic P450 inhibitors, SKF 525A, metyrapone, and carbon monoxide provided a significant reduction in the in vitro formation of DEA by human hepatic microsomes. Amiodarone N-deethylase activities expressed by intrinsic clearance values were similar in all the livers used, although two livers were genotyped as extensive and one as a poor metabolizer for the cytochrome P450 CYP2D6 gene¹. DEA production was strongly inhibited (more than 80%) by the anti-P450 3A4 antibody, but not by anti-LKM1-positive serum. It seems therefore that the P450 3A subfamily is certainly implicated in human hepatic amiodarone N-deethylation.     

Effects of chronic amiodarone treatment on cat myocardial phospholipid content and on in vitro phospholipid catabolism

Amiodarone is used extensively for the chronic treatment of life-threatening arrhythmias caused by ischemic heart disease. However, chronic therapy with this agent results in phospholipidosis in various tissues and it has been suggested that the inhibition of lysosomal phospholipase A by this drug contributes to this abnormality. Exogenous amiodarone has been shown to inhibit purified rat liver lysosomal phospholipase A₁, as well as acid phospholipase activities of alveolar macrophage homogenates and those of snake venom phospholipase A₂ and bacterial phospholipase C. The effects of drug treatment on heart have not been explored. The results described here demonstrate that amiodarone also significantly increases (37%, p < 0.001) phospholipid content in cat hearts. This increase is proportionately distributed to all major phospholipid classes, with the exception of sphingomyelin which appears to increase more than the others. In addition, the data also show that following amiodarone treatment, the endogenous drug levels in the heart were sufficient to reduce in vitro losses of membrane phospholipid at 37°C by inhibiting a variety of endogenous phospholipases at physiological (7.4), ischemic (6.2) and acidic (5.0) pH values. This protection is more pronounced at acidic pH values than at physiological pH. Endogenous amiodarone also affects myocardial phospholipase activities towards exogenous phosphatidylcholine and again the extent of inhibition is more at acidic pH. These results suggest that amiodarone induces phospholipidosis in the heart by inhibiting phospholipid catabolism and that its antiarrhythmic properties may reside in its ability to modulate alkaline, neutral and acid phospholipase activities in ischemia. To what extent amiodarone metabolites (desethylamiodarone and bis-desethylamiodarone) are involved in these actions remains to be determined.     

Repeated amiodarone exposure in the rat: toxicity and effects on hepatic and extrahepatic monooxygenase activities

Amiodarone is a potent and efficacious antiarrhythmic agent, yet associated with its use are life-threatening pulmonary fibrosis and hepatotoxicity. We have investigated the susceptibility of the male Sprague-Dawley rat to pulmonary and hepatic toxicity after repeated exposure to amiodarone and the effects of such exposure on hepatic and extrahepatic drug metabolizing enzymes. Animals received amiodarone (200 mg.kg-1.day-1 i.p., 5 days/week) for 1 week followed by 150 mg.kg-1.day-1 (5 days/week) for 3 additional weeks. No signs of pulmonary fibrosis or hepatotoxicity were observed, based on histological examination, lung hydroxyproline content, and plasma alanine aminotransferase activity. Analysis of tissues revealed extensive accumulation of amiodarone and desethylamiodarone in lung and liver, but concentrations were significantly lower in animals treated for 4 weeks than for 1 week. In a separate experiment, rats received amiodarone 150 mg.kg-1.day-1 i.p. (5 days/week) for 1 or 4 weeks. No differences in tissue concentrations of amiodarone and desethylamiodarone were detected between animals treated for 1 or 4 weeks. This regimen did not affect hepatic or extrahepatic monooxygenase activities. These results indicate that, in the male Sprague-Dawley rat, there is no observable pulmonary or hepatic toxicity following short-term amiodarone exposure, and there is enhanced elimination of amiodarone and desethylamiodarone when the daily dose of amiodarone is decreased after 1 week from 200 to 150 mg/kg.     

Interaction of amiodarone and its analogs with calmodulin

Benzofurans have important actions on the electrical properties of myocardium; the biochemical basis of those actions is not known. Crystallographic examination of these compounds has revealed that benzofurans share structural homologies with the traditional calmodulin antagonists N-(6-aminohexyl)-5-chloro-1-naphthalene and trifluoperazine. In the present study, the ability of amiodarone, desethylamiodarone, and benziodarone to displace the fluorescent ligand 8-anilino-1-naphthalene sulfonic acid (ANS) from calmodulin, to modulate the fluorescence emission of dansylcalmodulin, and to inhibit the activation by calmodulin of bovine brain cyclic nucleotide phosphodiesterase and human erythrocyte membrane Ca2+-ATPase were investigated at concentrations ranging from 10(-8) to 10(-6) M. These benzofurans displaced ANS from calmodulin with nearly equal efficiency upon forming a 1:1 complex with that protein. Each of these compounds also produced a decreased fluorescence emission of dansylcalmodulin, but with relative efficiencies being desethylamiodarone greater than amiodarone greater than benziodarone. Amiodarone and desethylamiodarone inhibited calmodulin-stimulable phosphodiesterase activity with similar potencies. Amiodarone and benziodarone inhibited calmodulin-stimulable Ca2+-ATPase activity equally, but desethylamiodarone had no effect. The observed differential effects of the amiodarone analogs suggest that calmodulin may possess multiple benzofuran-binding sites that are recognized by specific targets and ligands of this Ca2+-binding protein and that the cellular action of amiodarone and its analogs may reflect calmodulin antagonism.     

Growth,development, and reassessment of hypothyroid infants diagnosed by screening.

Thirty]six neonates in whom hypothyroidism was diagnosed after thyroid stimulating hormone screening were reassessed at 1 year. All had grown satisfactorily and the mental development scores were normal in all except two. Treatment was withdrawn in 32 and persistent hypothyroidism was confirmed in 31 cases. Thyroid stimulating hormone concentrations were raised in one-third of cases before the withdrawal of treatment and this was associated with generally lower concentrations of serum thyroxine (T4) and smaller doses of L-thyroxine than in those cases with normal concentrations of thyroid stimulating hormone. In treating congenital hypothyroidism, serum T4 concentrations should be monitored regularly and the dose of thyroxine adjusted to maintain serum T4 in the upper part of the reference range.     

High-performance liquid chromatographic assay for amiodarone N-deethylation activity in human liver microsomes using solid-phase extraction

A selective and sensitive assay for amiodarone N-deethylation activity in human liver microsomes by high-performance liquid chromatography (HPLC) with UV detection is reported. The extraction of desethylamiodarone from incubation samples was performed by means of an original solid-phase extraction (SPE) procedure using a polymeric reversed-phase sorbent (Oasis HLB). The method was validated for the determination of desethylamiodarone with respect to specificity, linearity, precision, accuracy, recovery, limit of quantitation and stability. Amiodarone N-deethylation activity from low to high substrate concentrations using human liver microsomes was precisely determined without a concentration step. This method is applicable to the study in vitro of the metabolism of amiodarone.     

胺碘酮致甲状腺功能异常的诊治进展

胺碘酮是治疗心律失常的常用药物。但由于其富含碘及自身固有的特性,可导致一系列甲状腺功能的紊乱,甚至引发明显的甲状腺功能减退（甲减）或甲状腺功能亢进（甲亢）。对于胺碘酮所致甲减（AIH）的诊断和治疗目前比较清晰,但对胺碘酮所致甲亢（AIT）的诊断、鉴别其亚型及治疗有一定的难度。     

Functional Effects of Short-Term Treatment with Amiodarone on Thyroid Tissues of the Rabbit

The effect of short-term treatment with Amiodarone on thyroid gland tissue was studied in a group of 26 New Zealand albino rabbits. Ten rabbits were left untreated and served as controls; the remaining animals were treated with 10 mg/kg/day Amiodarone. The serum levels of serum triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH) levels were measured at days 0 (baseline), 7, 30, and 45. The serum selenium levels were also measured, but only on days 0 and 45 of the experiment. At the end of the experiment the animals were sacrificed and the levels of selenium, T3, T4, and iodine were determined in thyroid tissue. After 30 days treatment the values of T3 were significantly lower than those of the untreated controls or the baseline levels (p < 0.001). The T4 level was significantly lower and the TSH value was significantly higher after 45 days of Amiodarone (p < 0.001). In thyroid tissue the T3, T4, and iodine levels were significantly higher in the treated group when compared to untreated controls (p < 0.05). These results show that Amiodarone induces changes in the hormone levels in both serum and thyroid tissues, as well as in the amount of iodine taken up by the thyroid gland in rabbits.     

Graves' ophthalmopathy and subclinical hypothyroidism: diagnostic value of the thyrotropin releasing hormone test.

Five patients with Graves'' ophthalmopathy and no previously documented clinical or laboratory evidence of hyperthyroidism were studied. Their serum levels of thyroxine and triiodothyronine (T3) and their T3 uptake were normal. Although the baseline serum level of thyrotropin (TSH) was normal in two patients, it was increased on the other three, and when TSH releasing hormone (TRH) was administered the T3 response was impaired in three patients and the TSH response was exaggerated in all five. These findings facilitated the diagnosis of subclinical hypothyroidism and distinguished the patients from those with Graves'' ophthalmopathy and normal thyroid function or subclinical hyperthyroidism. Thyroid antibodies were detected in the serum of four of the five patients, suggesting the coexistence of chronic autoimmune thyroiditis; this disorder could account in part for the subclinical hypothyroidism, which was even present in the two patients in whom thyroid-stimulating immunoglobulin was found in the serum. These observations indicate the value of a TRH stimulation test in detecting subclinical hypothyroidism in patients with Graves'' ophthalmopathy who appear from clinical and routine laboratory studies to have normal thyroid function but could have normal function or subclinical hyperthyroidism.     

Lowering of T3 and rise in reverse T3 induced by hyperglucagonemia: altered thyroid hormone metabolism, not altered release of thyroid hormones

Recently we reported that hyperglucagonemia induced by glucagon infusion causes a decline in serum T3 and a rise in reverse T3 in euthyroid healthy volunteers. These changes in T3 and rT3 levels were attributed to altered T4 metabolism in peripheral tissues. However, the contribution of altered release of thyroid hormones by the thyroid gland could not be excluded. Since the release of thyroid hormones is inhibited in primary hypothyroidism and is almost totally suppressed following L-thyroxine replacement therapy, we studied thyroid hormone levels for up to 6 hours after intravenous administration of glucagon in subjects with primary hypothyroidism who were rendered euthyroid by appropriate L-thyroxine replacement therapy for several years. A control study was conducted using normal saline infusion. Plasma glucose rose promptly following glucagon administration demonstrating its physiologic effect. Serum T4, Free T4, and T3 resin uptake were not altered during both studies. Glucagon infusion induced a significant decline in serum T3 (P less than 0.05) and a marked rise in rT3 (P less than 0.05) whereas saline administration caused no alterations in T3 or rT3 levels. Thus the changes in T3 and rT3 were significantly different during glucagon study when compared to saline infusion. (P less than 0.01 for both comparisons). Since, the release of thyroid hormones is suppressed by exogenous LT4 administration in these subjects; we conclude that changes in serum T3 and rT3 observed following glucagon administration reflect altered thyroid hormone metabolism in peripheral tissues and not altered release by the thyroid gland.     

Treatment of amiodarone induced hyperthyroidism with potassium perchlorate and methimazole during amiodarone treatment.

To exploit the antiarrhythmic effect of amiodarone when patients develop the side effect of thyrotoxicosis three patients with hyperthyroidism induced by amiodarone were given simultaneously 1 g potassium perchlorate a day for 40 days and a starting dose of 40 mg methimazole a day while they continued to take amiodarone. As hyperthyroidism might have recurred after potassium perchlorate treatment was stopped the dose of methimazole was not reduced until biochemical hypothyroidism (raised thyroid stimulating hormone concentrations) was achieved. The patients became euthyroid (free triiodothyronine concentration returned to normal values) in two to five weeks and hypothyroid in 10 to 14 weeks. One patient became euthyroid while taking 5 mg methimazole a day and 600 mg amiodarone weekly; the two others required substitution treatment with thyroxine sodium while taking 5 mg methimazole or 50 mg propylthiouracil (because of an allergic reaction to methimazole) and 2100 or 1400 mg amiodarone weekly. Hyperthyroidism induced by amiodarone may be treated with potassium perchlorate and methimazole given simultaneously while treatment with amiodarone is continued.     

Late-onset thyrotoxicosis after the cessation of amiodarone

IntroductionAmiodarone is a highly effective antiarrhythmic-drug with well recognized toxic side-effects. The effects of the drug late in patients with atrial fibrillation (AF) is not well described.Methods and resultsWe present a single centre prospectively collected series of patients with thyrotoxicosis occurring late after the cessation of amiodarone. Between 2006 and 2018, 8 patients were identified with amiodarone induced thyrotoxicosis (AIT). Amiodarone was prescribed for AF in 7 patients and ventricular tachycardia in 1 patient. Mean duration of therapy was 329 [42–1092] days, mean dose of 200 ± 103.5 mg/day. Amiodarone use was short term (<140 days) in 4 of the 8 cases, with one treated for 42 days. Patients presented with symptoms including weight loss, tremors, palpitations, AF, sweats all indicative of AIT at a median of 347 [60–967] days post cessation. Thyroid function testing confirmed suppressed thyroid stimulating hormone and elevated T levels in all patients. Nuclear thyroid imaging in all cases demonstrated low uptake of iodine indicative of Type II AIT. All patients recovered following pharmaceutical treatment with Carbimazole and Prednisolone.ConclusionsWe describe a series of patients with late thyrotoxicosis after exposure to amiodarone. Our findings highlight the need for a high-index of clinical suspicion for AIT regardless of treatment duration or time after cessation of amiodarone.     

In vitro inhibition of lysosomal phospholipase A1 of rat lung by amiodarone and desethylamiodarone

Amiodarone causes phospholipid storage in the lysosomes of various types of lung cell in animals and man. It has been proposed that this is due to its ability to inhibit lysosomal phospholipase A. To investigate this further, a crude lysosomal fraction from rat lung was prepared and phospholipase A was isolated and its positional specificity was determined. Analysis of the products formed after incubation with 2-[1-14C]oleoylphosphatidylcholine showed that only phospholipase A1 activity is present. This soluble preparation of lung lysosomal phospholipase A1 was used to study inhibition by amiodarone and desethylamiodarone, in vitro. Both were extremely potent inhibitors of the lung acid phospholipase A1. To evaluate the levels of amiodarone in lung lysosomes, rats were treated with the agent for 3 days and the combined mitochondrial/lysosomal fraction of lung tissue was prepared by differential centrifugation. This fraction had been shown previously to be highly enriched in amiodarone. Purified mitochondria and lysosomes were isolated from the combined mitochondrial/lysosomal fraction with Percoll gradients and analyzed for their drug content by HPLC. Amiodarone and desethylamiodarone were present in roughly equal amounts, relative to protein, in mitochondria and lysosomes, respectively. Amiodarone appears to differ from other cationic amphiphilic drugs which cause lipidosis because the latter are more highly lysosomotropic. Although amiodarone does not appear to be highly lysosomotropic in lung, it causes lysosomal phospholipid storage because of its ability to concentrate in lung and because it inhibits lysosomal phospholipase A to a much greater extent than other cationic amphiphiles such as diethylaminoethoxyhexestrol, chloroquine and chlorphentermine.