Clinical pharmacokinetics of cyclosporin

Pharmac. Ther. Vol. 42, pp. 135-156, 1989 Printed in Great Britain. All rights reserved

0163-7258/89 S0.00 + 0.50 Copyright © 1989 Pergamon Press pie

Associate Editor: M. J. BRODIE

CLINICAL

PHARMACOKINETICS CYCLOSPORIN

OF

MARGARET A . M C M I L L A N Renal Unit, Western Infirmary, Glasgow G I I 6NT, Scotland

1. INTRODUCTION Cyclosporin is a cyclic undecapeptide of fungal origin and a potent immunosuppressive agent (Fig. 1). Its use in organ transplantation has transformed the outlook for allografts from unrelated donors (European Multicentre Trial Group, 1983). There remain, however, problems in its use. Neither the therapeutic nor the toxic effects correspond well to the dose administered. Of the many side effects, the most distressing--to the physician--is nephrotoxicity. This poses particular problems in renal transplantation, where it may be hard to distinguish confidently between rejection and cyclosporin toxicity. There is also concern that short-term transplant success may be partly offset by longer-term failure due to progressive cyclosporin toxicity. The problem posed by nephrotoxicity has proved a potent stimulus to research into therapeutic drug monitoring, and into pharmacokinetic and pharmacodynamic parameters which might enable prediction of the therapeutic dose of cyclosporin for the individual patient (Kahan, 1985; Kahan et al., 1986). All the pharmacokinetic studies share the limitations of the analytical methods used; these methods will be examined first. 2. ANALYTICAL METHODS FOR CYCLOSPORIN 2.1. INTRODUCTION

The two types of assay available for cyclosporin are radioimmunoassay (RIA) and high performance liquid chromatography (HPLC). These were recently reviewed in the U.S.A. by the Task Force on Cyclosporine Monitoring (1987), who noted that, "the controversy is intense regarding the acceptability of either", and concluded that, "considering the analytical difficulties associated with measurement of cyclosporin A, whether by RIA or HPLC, participation in a quality assurance programme ... is highly recommended." 2.2. RIA The crux of the controversy between the proponents of the two assay methods is the specificity, or lack of it, of the original antisera used for the RIA (Donatsch et al., 1981). These antisera were raised in rabbits, then later in sheep, but with all types both parent drug and metabolites were detected. The therapeutic and toxic potentials of the metabolites, particularly the major metabolite, numbered 17, are disputed (Rosario et al., 1986a,b; Schlitt et al., 1987; Yee et al., 1986a). What is clear is that the relative proportions of parent drug and metabolites detected by RIA will be affected by interindividual variations in drug metabolism and clearance of metabolites (Tables 1 and 2). This complicates both clinical interpretations of RIA results and scientific interpretation of pharmacokinetic studies performed using this assay method. Recently, the pharmaceutical company which produces cyclosporin (Sandoz Inc.) has developed a monoclonal antibody which appears to be specific for the parent drug a,r 4:/i-i.

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(Quesniaux et aL, 1986). RIA based on this antibody is now being widely introduced, with encouraging results. Cyclosporin concentrations derived with the monoclonal RIA appear to be comparable to those obtained by HPLC (Holt, 1986; Quesniaux et al., 1987; Kwan et al., 1987b). The monoclonal RIA offers the specificity of HPLC without its technical disadvantages (see Section 2.3), and is likely to become the standard assay method. The major complaint against the RIA method is its lack of specificity, but there are also technical problems in its use. The commercially available kit uses tritium-labeled cyclosporin, so has limited stability. Samples often have to be diluted, as concentrations above the linear range of the standard curve are common, particularly in patients with liver disease. Although a U.K. Quality Assessment Scheme showed wide variation in results obtained for standard samples, within-assay coefficients of variation (14-18%) were better than those for HPLC (34-47%) (Holt, 1986). RIA has the advantages of being both rapid and sensitive (Ptachcinski et al., 1986b). 2.3. HPLC The many approaches to measurement of cyclosporin by HPLC are reviewed by the Task Force on Cyclosporine Monitoring (1987). None of the variations on this technique eliminates its major drawback, that HPLC is more demanding of laboratory time, equipment and expertise. The clinical demand for rapid analysis of numerous samples has encouraged the choice of RIA. Some transplant centres have opted for the relative specificity of HPLC, particularly when undertaking pharmacokinetic studies. 2.4. COMPARISONBETWEENRESULTSOBTAINEDBY RIA AND HPLC Results obtained by RIA with polyclonal antisera (cyclosporin plus metabolites) are consistently higher than those obtained by HPLC (parent drug alone), but the ratio between the two sets of results varies with the relative proportions of drug and metabolites. The greater the time interval between last dose and sampling, the higher the proportion of metabolites, and the higher the ratio of results of RIA: HPLC. Serial measurements used to adjust cyclosporin dosage should therefore be taken at a standard time interval after

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the last dose. Other drugs or diseases which affect the metabolism or excretion of cyclosporin will also influence the RIA:HPLC ratio (see Sections 5 and 6). Reported values for the ratio are as low as 1:1 and as high as 15:1 (Ptachcinski et al., 1986b). Average values for normal subjects are of the order of 2:1 flask Force on Cyclosporine Monitoring, 1987). Renal transplant patients without hepatic or cardiac failure fall in a similar range. The results of Hamilton et al. (1987) are fairly typical, with RIA: HPLC ratios for renal transplant recipients less than 2.7:1 and a mean value of 3.9 : 1 for heart and liver transplant recipients. The highest ratios are found shortly after liver transplantation, and fall as liver function improves (Aziz et al., 1986; Wallemacq et al., 1987; Task Force on Cyclosporine Monitoring, 1987). 2.5. SAMPLINGFOR MEASUREMENTOF CYCLOSPORINLEVELS Cyclosporin is measured commonly in peripheral blood. Because cyclosporin is highly lipophilic, it may adhere to plastic cannulae. Blifield and Ettenger (1987) recommended that samples should not be withdrawn from an intravenous cannula through which cyclosporin has been administered. Cyclosporin may also adhere to laboratory equipment, affecting assay results (Task Force on Cyclosporine Monitoring, 1987). EDTA is preferable to heparin as anticoagulant. Clots large enough to affect the assay result form more commonly with heparin, especially with freeze--thawing or prolonged delay before analysis (Prasad et al., 1985; Potter and Self, 1986). Whole blood may be a better sample matrix than plasma for analytical reasons (Task Force for Cyclosporine Monitoring, 1987). Cyclosporin in serum is stable at room temperature for up to 7 days, and at -20°C for up to 5 months (Smith et al., 1983). This however depends on rapid separation from the cellular component before the sample cools. In a sample of whole blood at 21°C with a cyclosporin concentration of 500 ng/ml, 60% of the drug is bound to erythrocytes. As the sample cools, the affinity of the erythrocytes for cyclosporin increases (Niederberger et al., 1983). Plasma separated at room temperature may give a misleadingly low and inconsistent impression of the circulating plasma concentration. If samples of whole blood cool between clinic and laboratory, or need to be stored before analysis, they may be reheated to 37°C, allowing re-equilibration of drug between plasma and cells, without apparent loss of accuracy of assay result (Smith et al., 1983; Niederberger et al., 1983). 2.6. INTERPRETATIONOF ASSAY RESULTS 2.6.1. Significance of Measurements Interpretation of measurements of cyclosporin is dependent both on choice of matrix and on method of analysis. As discussed in Section 2.2, the clinical contribution of cyclosporin metabolites is ill-defined, but they contribute significantly to results obtained by RIA. RIA results for a patient should be considered in the context of the patient's clinical condition, particularly where hepatic or cardiac impairment may reduce cyclosporin clearance (Ptachcinski et al., 1986b). 2.6.2. Effect of Haematocrit Just as laboratory methods allow for extensive binding of cyclosporin to erythrocytes, interpretation of assay results must include consideration of the patient's haematocrit. Robson et aL (1984a) noted increases in the plasma cyclosporin levels in four patients when the haematocrit fell. Rosano (1985) reported an inverse correlation between the haematocrit and the plasma fraction of cyclosporin in the circulating blood, although with variation among the results for individual patients. A 10% rise in haematocrit was associated with a fall in the plasma portion of cyclosporin of around 12%. The distribution between plasma and erythrocytes was unaffected by plasma lipids in this study.

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2.6.3. Effect o f Lipoprotein Profile Cyclosporin dissolves in the lipophilic portion of lipoprotein molecules and binds to all classes of circulating human lipoproteins (Sgoutas et aL, 1986; Zaghloul et aL, 1987). In plasma at 4°C, Lemaire and Tillement (1982) showed that cyclosporin was 70% bound. This increased to 95% binding at 20°C. In healthy fasting individuals, only 15% of the binding is to non-lipoproteins (Sgoutas et al., 1986). The remainder is divided between HDL (46%), LDL (31%), and VLDL (8%). In the same study the appearance of chylomicrons after a meal was associated with binding of 7% of the total. Values were similar for patients on regular cyclosporin therapy. The clinical significance of these results is that variations in the lipid profiles of patients on cyclosporin may affect the interpretation of cyclosporin blood measurements. For example, in a study in bone marrow transplant recipients, Nemunaitis et al. (1986) noted a correlation between raised serum triglyceride levels and high cyclosporin levels which were not associated with nephrotoxicity. They suggested that the correct course of action in this situation was not to withhold cyclosporin without first checking triglyceride levels. Tufveson et al. (1986) claimed that the lipoprotein profile could help to estimate the cyclosporin dose required by a patient. Verrill et aL (1987) studied a renal transplant patient with Type V hyperlipoproteinaemia. Not only was cyclosporin extensively bound, but in vitro studies showed that cyclosporin remained bound to the lipid fraction and did not re-equilibrate with either lymphocytes or sections or renal tissue. This again suggests that higher plasma levels are required to allow for hyperlipidaemia and to achieve adequate levels of cyclosporin at its sites of action. A logical extension of these findings would be that cyclosporin levels should be interpreted similarly in patients receiving parenteral feeding with Intralipid. No interaction between cyclosporin and Intralipid was found, however, in a study in dogs (Wassef et aL, 1986). 2.7. THERAPEUTIC CONCENTRATION RANGES The values for cyclosporin concentration which are regarded as therapeutic depend on the type of assay, the sample matrix, the patient's haematocrit and lipid profile, and concomitant drug therapy. The addition to cyclosporin of other immunosuppressive agents, such as prednisolone, may provide adequate immunosuppression with lower cyclosporin concentrations (Forwell et al., 1987). Centres using different immunosuppressive protocols may thus disagree on desirable concentrations. Different patients appear to require different cyclosporin levels to avoid the twin perils of rejection and nephrotoxicity, and there is no reliable immunological method to optimise the cyclosporin dose (Kahan, 1985; Bozkurt et al., 1987). The ranges quoted by Kahan (1985) for whole blood in the early period after renal transplantation are 300-800 ng/ml (RIA) and 100-150 ng/ml (HPLC). Six months after transplantation, a range of 150--400ng/ml by RIA is adequate. With the specific monoclonal RIA, Kwan et al. (1987b) advocate a therapeutic range of 95-205 ng/ml in whole blood, to correspond to their range of 250-500 ng/ml with the polyclonal RIA. The dose required to achieve this varies considerably among patients. Although an initial oral dose for renal transplant patients is often around 15 mg/kg, doses lower than 5 mg/kg may be adequate after several months (Forwell et al., 1987). 3. ADMINISTRATION AND ABSORPTION 3.1. ROUTESOF ADMINISTRATION Cyclosporin is poorly absorbed after intramuscular administration (Keown et aL, 1981) and is therefore administered either orally or intravenously. Subcutaneous administration gives the most consistent pattern of absorption in the rat, but has not been used in man (Wassef et al., 1985).

Clinical pharmacokinetics of cyclosporin

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3.2 ORAL ADMINISTP,~TION 3.2.1. Pattern of Absorption After oral administration the absorption of cyclosporin from the gut is slow, incomplete, and varies widely among individual patients (Table 1). The site of absorption is the upper part of the small intestine. There is broad agreement that the mean time from ingestion to peak cyclosporin blood level is around 4 hr (Table 1). The inter-patient variation is striking. Kahan (1985) quotes a range in renal transplant patients between 1 and 8 hr. 3.2.2. Effect of Gut Motility Gastrointestinal motility affects absorption. While small amounts of diarrhoea from any cause may reduce absorption sharply (Atkinson et al., 1984, Table 1), the moderate increase in rate of gastric emptying induced by metoclopramide may increase the bioavailability of cyclosporin (Wadhwa et al., 1987a,b). Conversely, in rats Ueda et al. (1983) found bioavailability reduced by impaired gastric emptying. This problem may be particularly relevant in patients with abnormal gastric emptying, for example due to diabetic autonomic neuropathy. 3.2.3. Effect of Bile Flow Absorption appears to be dependent on bile flow but the precise physiological mechanism of absorption is unknown. Kahan (1985) quotes an unpublished report of the abrogation of cyclosporin immunosuppression after concomitant therapy with cholestyramine and suggests that bile solubilization of cyclosporin is necessary to enable cyclosporin to mix with the aqueous phase at the absorptive surface. Ericzon et al. (1987) showed that the administration of bile salts increased cyclosporin absorption in dogs. An inter-relationship between cyclosporin absorption and biliary flow has been demonstrated in various experimental models. Using an isolated perfused rat liver model-----eliminating, for example, possible neuroendocrine effects on absorption--Rotolo et al. (1986) showed that cyclosporin itself reduced bile flow and bild acid absorption, limiting perhaps its own absorption. In dogs, bile duct ligation (Takaya et ai., 1987) and biliary diversion (Ericzon et al., 1987) reduce cyclosporin absorption from the gut. Subtotal hepatectomy, resulting in decreased bile production, decreases cyclosporin bioavailability in dogs (Ericzon et aL, 1987). In liver transplant patients, the poor cyclosporin absorption associated with external bile drainage improves sharply when the T-tube is clamped. In a study from the Pittsburgh group, cyclosporin levels rose by a factor of five after clamping (Venkataramanan et al., 1985). A study of 10 patients given cyclosporin for primary biliary cirrhosis failed to show a sustained difference in absorption from published results obtained using patients with normal bile flow (Robson et al., 1984b). It is possible that the small sample size and the wide inter-patient variation in this study might have affected the conclusions reached. 3.2.4. Effect of Food If bile flow is so important, can the absorption of cyclosporin be increased by stimulating bile flow with food? The initial advice to patients was to take cyelosporin mixed with milk. This outstandingly unpalatable mixture appeared, in a small study in normal volunteers by Johnston et al. (1986), to be absorbed no better than cyclosporin alone, or cyclosporin with fruit juice. In other studies absorption was reduced by wine (Ota, 1983) and slowed by a soybean nutritional supplement (Kahan, 1985). Ptachcinski et al. (1985c) showed that absorption was greater, if no quicker, when cyclosporin was given with a full breakfast rather than just a milky drink. The elimination half-life was the same, with or without food.

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Ptachcinski et al. (1985c) suggested two further mechanisms to explain the enhancement of cyclosporin absorption by food. First, that cyclosporin blood measurements increased because of the increased circulating lipoprotein levels after a meal. Secondly, they speculated that the increased absorption was mediated by the lymphatic system, with increased lymph flow after food. 3.2.5. Role o f Lymphatic Absorption The topic of lymphatic absorption was raised by Albrechtsen et al. (1985). Oral, and not intravenous, cyclosporin given to rats led to a drug concentration in lymph 10 times that in peripheral blood. While significant lymphatic absorption might also be an ingenious way for the drug to reach the lymphocytes, Albrechtsen et al. managed to recover little of the total dose from the lymphatic system. Ueda et al. (1983) found that only 0.4% of a dose of cyclosporin was transported via the thoracic duct. The data from Albrechtsen et al. would have been strengthened by compatible drug levels from the portal blood. Gridelli et al. (1986) did analyze portal blood while comparing oral and intravenous administration in the dog. Cyclosporin metabolites were found in the portal vein, leading the authors to speculate that there might be some metabolism of cyclosporin in the gut itself. 3.2.6. Duration o f Cyclosporin Therapy Another influence on the extent of absorption appears to be the time after transplantation and commencement of the drug. In a study of 21 renal transplant patients, Tufveson et al. (1986) found that bioavailability after an oral dose increased by 50% during the first 3 months after transplantation. Attributing this change to increased absorption, they argued that the change could be predicted from changes in a patient's lipoprotein pattern. Differences in absorption may also be responsible for the finding of Vereerstraeten et al. (1986) that twice daily dosage of cyclosporin reduced the total dose required to achieve a given trough drug level. Ptachcinski et al. (1986b) suggested that for some patients absorption is dose-dependent. 3.2.7. Oral Bioavailability Bioavailability, representing the percentage of a dose of cyclosporin that reaches the systemic circulation, and calculated from data from paired oral and intravenous administration, ranges from 1% (Kahan, 1985) to 89% (Ptachcinski et al., 1986b). Excluding patients with markedly abnormal gut motility or bile flow, the mean bioavailabilities, within 3 months of transplantation, for the groups of organ transplant recipients in Table 1 are similar at around 30%. Although poor bioavailability has generally been attributed to poor absorption, another factor may, as suggested from rat work by Ueda et al. (1984), be a significant 'first-pass' effect, with newly-absorbed cyclosporin in the portal circulation extensively metabolised by the liver. 4. DISTRIBUTION 4.1. DISTRIBUTIONIN BLOOD Much of the attention paid to the distribution of cyclosporin has been to its distribution amongst blood components, especially red corpuscles and the lipoprotein fraction. This is related to the uncertainties surrounding optimal therapeutic blood monitoring, and is described in more detail in Section 2. Lemaire and Tillement (1982) estimated that 30-40% of the drug was found in the plasma and that almost all of this was bound in the protein fraction. Cyclosporin itself increases lipoprotein concentrations (Harris et al., 1986), affecting its own distribution. Leucocytes bound 10-20% of the cyclosporin, but became saturated at blood levels of the drug greater than 100ng/ml, and so their relative

Clinical pharmacokineticsof cyclosporin

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contribution was greatest at low cyclosporin concentrations. The rest of the cyclosporin bound to erythrocytes, as discussed in Section 2. 4.2. DISTRIBUTIONIN OTHERBODYFLUIDS Interest in the use of cyclosporin for autoimmune disease has prompted study in areas other than transplantation. Considering use of the drug in multiple sclerosis, Fazakerley and Webb (1985) found that cyclosporin did not cross the blood-brain barrier in significant amounts. Palestine et al. (1985) studied cyclosporin penetration into the anterior chamber of the eye and into cerebrospinal fluid. In none of the 6 patients studied did cyclosporin appear to cross the blood-brain barrier, and only in low concentrations was it found in the anterior chamber. Similar intraocular concentrations were achieved with topical cyclosporin in rabbits (Palestine et al., 1985). Flechner et al. (1985) had the opportunity to study a transplant recipient who had a successful pregnancy while on cyclosporin. The cyclosporin concentration in amniotic fluid was similar to that in the mother's peripheral blood and the neonate's lymphocytes showed reduced responsiveness in mixed lymphocyte culture. Cyclosporin was also detectable in breast milk. 4.3. DISTRIBUTIONINTOTISSUES In keeping with the lipophilic nature of cyclosporin, the drug accumulates in body fat. In eight patients with chronic renal failure given a single oral dose of cyclosporin, the area under the drug concentration/time curve correlated not with total body weight but with skinfold thickness (Waters et al., 1986). Accumulation in fat may explain the increased volume of distribution of cyclosporin noted by Kahan et al. (1986) in women. Using intravenous tritiated cyclosporin, Maurer et al. (1984) showed the heaviest accumulation of radiation in the liver and, in descending order, fat, kidney, reticuloendothelial and endocrine systems, and blood, with negligible recording from the central nervous system. Ryffel et al. (1986b) were less successful in their attempt to locate the intrarenal site of cyclosporin nephrotoxicity using a specific stain. 4.4. VOLUMEOF DISTRIBUTION The volume of distribution represents the size of the compartment required to account for the total amount of drug in the body, if it were present in the same concentration as in the plasma. One might expect a large volume of distribution for cyclosporin because of its lipid solubility, extensive tissue binding, and loose binding to plasma proteins (Kahan, 1985). Estimates of the total volume of distribution of cyclosporin vary (Table 2). In kidney transplant recipients Kahan (1985) reports a mean ( + standard deviation) volume of 8.7 ( + 6.2) 1/kg, and associates this with a distribution space of around 6001 (results obtained by RIA). The Pittsburgh group quotes a mean volume, obtained by HPLC, for renal transplant patients of 4.5 ( + 3.6) l/kg (Ptachcinski et al., 1986b). They give mean volumes of 3.9 l/kg for patients with liver disease, 1.2 l/kg for normal volunteers, and, lowest of all, 0.91/kg for children with cardiac failure. It is perhaps surprising that the values obtained by HPLC are so much lower, even in the comparable group of renal transplant recipients. As the metabolites of cyclosporin are less lipid soluble than the parent drug, they might be expected to bring down the volume of distribution when measured by RIA. 5. ELIMINATION 5.1. INTRODUCTION Elimination of cyclosporin takes place by metabolism in the liver and excretion of metabolites in the bile (Kahan, 1985). Elimination characteristics in different categories of

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patients are shown in Table 1 (after oral administration) and Table 2 (after intravenous administration). Cyclosporin elimination follows first-order kinetics, with a constant fraction of drug eliminated per unit of time (Kahan, 1985). Any disease or drug affecting hepatic or biliary function alters the metabolism and excretion of cyclosporin. 5.2. METABOLISM

5.2.1. Hepatic Metabolism Cyclosporin is extensively metabolised in the liver (Maurer et al., 1984). It has been estimated that as much as 50% of a dose of cyclosporin may be extracted from the blood during its first passage through the liver (Kahan, 1985). Changes in liver blood flow may therefore affect cyclosporin metabolism (see Fig. 2). 5.2.2. Variation with Age and Sex Children show a higher cyclosporin clearance than adults (Table 2), necessitating larger and more frequent doses (Nieberger et al., 1986; Yee et al., 1986b). This may be paralleled by a lower incidence of nephrotoxicity (Lindholm et al., 1987). Kahan et al. (1986) reported a lower rate of clearance of cyclosporin in patients aged over 45 years. There are no studies in the elderly but one might expect further dose reduction to be necessary. Women appear to clear cyclosporin more slowly than men (Kahan et al., 1986). Some of these variations may be related to variations in hepatic blood flow. 5.2.3. Variation with Dosage Regimen Differences in timing and distribution of drug doses may alter drug metabolism. Twice daily oral administration of cyclosporin required only 56% of the total drug dose when compared to once daily administration (Vereerstraeten et al., 1986). The criterion used for comparison was serum trough concentration, which was assumed to be the criterion of most clinical relevance. This may be disputed, and Vereerstraeten et al. (1986) were unable to offer an explanation for their results. Also unexplained is the circadian variation of cyclosporin eliminations described in patients with liver and heart transplants by the Pittsburgh group (Venkataramanan et aL, 1986b; Ptachcinski et al., 1987a). Comparison of morning and evening dosage showed higher blood levels and lower clearance values after the daytime dose. The authors speculated that their results were due to circadian variation of intravascular lipoproteins or of hepatic microsomal enzymes. Type of resct.ton Monohydroxylation

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Clinicalpharmacokineticsof eyclosporin

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5.2.4. Variation with Time There are now several reports of cyclosporin requirements falling over the first few months after transplantation (defined, again, as the amount of cyclosporin required to achieve the same trough level). Henny et al. (1985) studied patients during the first three months after renal transplantation. Tufveson et al. (1986) found that cyclosporin bioavailability increased by 50%, and suggested that the change was related to changing lipid profiles, and perhaps to increased absorption rather than to changes in metabolism. Studies in rats by Cunningham et al. (1984), however, showed a fall in cyclosporin levels with time, without change of dose. 5.2.5. Metabolic Pathway Maurer et aL (1984) illustrated that the major changes during metabolism of cyclosporin are hydroxylation on amino acid alkyl carbons and demethylation of a peptide bond nitrogen. These changes suggest that the enzyme system involved in cyclosporin metabolism is the cytochrome P450-dependent system of hepatic microsomal monooxygenases. Further evidence is that drugs which are known to interact with this system interact both experimentally and clinically with cyclosporin. Drugs that induce enzyme activity accelerate cyclosporin metabolism, and those reducing or competing for active enzyme slow it down (see Table 3). Cunningham et al. (1985) demonstrated improvement of cyclosporin-induced nephrotoxicity in rats by induction of hepatic drug metabolism with phenobarbitone. Phenobarbitone abolished biochemical and histological nephrotoxicity, lowered the serum cyclosporin level, and induced UDP-glucuronyl transferase in addition to cytochrome P450. While induction of cyclosporin conjugation could be an alternative explanation for these results. Maurer et aL (1984) found no conjugated metabolites in rat urine. Cytochrome P450, and therefore cyclosporin metabolism, is affected via another mechanism by erythromycin. Although erythromycin induces the cytochrome P450 enzymes used in its own metabolism, it also appears to bind firmly to the enzyme forming an inactive complex (Danan et al., 1981; Larrey et al., 1983). Cyclosporin may also inhibit its own metabolism (Moochhala and Renton, 1986), perhaps through a similar 'suicide substrate' formed by the interaction between parent drug and enzyme (Burke and Whiting, 1986). 5.2.6. Extrahepatic Metabolism Although most of the cytochrome P450 enzymes are located in the liver, lesser amounts are found in other tissues, including the kidneys and the mucosa of the small intestine. This ties in with the suggestion by Gridelli that one reason for limited oral bioavailability of cyclosporin may be metabolism within the intestinal wall (Gridelli et al., 1986). 5.3. EXCRETION After the initialenzyme process, many drugs need to be conjugated to achieve both the necessary polarity and high molecular weight for biliary excretion. Hydroxylated TASLE 3. Drugs with Clinically Established Effects Cyclosporin Metabolism Decrease metabolism Increase metabolism (increasecyclosporin (decreasecyclosporin blood levels) blood levels) Diltiazem Carbamazepine Erythromycin Phenobarbitone Ketoconazole Phenytoin Methyltestosterone Rifampicin Norethisterone

on

146

M.A. MCMILLAN

cyclosporin metabolites, with molecular weights > 1200 can be excreted in the bile without further conjugation (Burke and Whiting, 1986). In liver transplant recipients, the total amount of cyclosporin excreted in the bile in one dosing interval is directly related to the output of bile (Venkataramanan et al., 1985). There is some enterohepatic recirculation of cyclosporin metabolites and most of the drug is ultimately excreted in the faeces (Kahan, 1985). In man, less than 10% of cyclosporin is excreted into the urine, again predominantly as metabolites (Burke and Whiting, 1986). So limited is the urinary excretion of cyclosporin that anuric patients do not require a lower dose in order to retain blood levels within the therapeutic range (Follath et al., 1983). 5.4. CLEARANCEOF CYCLOSPORINBY DIALYSIS Venkataramanan et al. (1984) studied the clearance of cyclosporin by haemodialysis. Less than 1% of a cyclosporin dose was cleared by a 4 hr haemodialysis. This was not unexpected in view of the drug's high molecular weight, extensive binding to cells and proteins, marked lipid solubility and large volume of distribution. There are no published reports of cyclosporin clearance by peritoneal dialysis.

6. INTERACTIONS WITH OTHER DRUGS 6.1. INTRODUCTION There are two major features of cyclosporin which make drug interaction clinically important. First, it shares with numerous other drugs metabolic pathways utilising the cytochrome P450 system. Secondly, drugs which do not affect cyclosporin kinetics may influence its nephrotoxicity. Drugs with clinically important interactions with cyclosporin are described in this section and listed in the Appendix. 6.2. VEHICLE INTERACTIONS Oral and intravenous preparations of cyclosporin are prepared with different vehicle bases, both mixtures of oil and alcohol. Allergic reactions to intravenous cyclosporin have been blamed squarely on its cremophor vehicle (Kahan, 1985), but there is little evidence to implicate the vehicle in drug interactions reported with cyclosporin. Possible exceptions are the anaesthetic agents atracurium and vercuronium. Gramstad et al. (1986) reported that cyclosporin therapy potentiated neuromuscular blockade by these drugs, and attributed this effect to vehicle rather than drug.

6.3. IMMUNOLOGICALINTERACTIONS Interest in the immunosuppressive potential of calcium channel blockade, and speculation that cyclosporin could affect cellular calcium transport, prompted in vitro work on the interaction between cyclosporin and calcium channel blocking drugs. McMillan et al. (1985) suggested that verapamil potentiates the immunosuppressive activity of cyclosporin, and went on to propose that the mechanism was the inhibition of protein kinase C-mediated events in lymphocyte activation (McMillan et al., 1987). McMillan et al. (1987) were careful to use intravenous verapamil, to eliminate any conceivable effect on cyclosporin absorption of verapamil-related changes in splanchnic blood flow. The work of Lindholm and Henricsson (1987) points to another possible factor: inhibition by verapamil of cytochrome P450, with corresponding rise in cyclosporin level. In the rat model of Liu et aL (1985), propranolol prolonged rat cardiac and islet graft survival when azathioprine was used as well, but antagonized survival when cyclosporin was used. There is no comparable work in man. Liu et al. (1985) offered no pharmacokinetic data for discussion of the apparent reduction by propranolol of the immunological effects of cyclosporin.

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Cyclosporin depresses T helper cell function. Versluis et al. (1986) compared the antibody response to influenza vaccine of two groups of patients with renal transplants. The cyclosporin-treated group developed less response than the azathioprine-treated group. Cyclosporin may be combined with other immunosuppressive agents to achieve more effective immunosuppression. The subject of interaction between cyclosporin and prednisolone is controversial, and is discussed more fully in Section 6.7. Azathioprine, anti-lymphocyte globulin and the monoclonal antibody OKT3 are all used with cyclosporin in organ transplantation. It is worth noting that these agents have no reported interactions with cyclosporin other than complementary immunosuppressive effects. 6.4. DRUGSAFFECTINGCYCLOSPORINNEPHROTOXICITY 6.4.1. Protection Against Nephrotoxicity The mechanism of cyclosporin-induced nephrotoxicity is unknown, hampering attempts to avert it pharmacologically without sacrificing therapeutic efficacy. Suzuki et al. (1987) suggest, from animal work, that nephrotoxicity is related to inhibition by cyclosporin of nucleic acid synthesis and cell membrane function, and that prednisolone may help to protect the kidney against damage. Codergocrine does not alter cyclosporin blood levels but may reduce nephrotoxicity, perhaps by influencing renal blood flow (Heinrichs et al., 1987). Renal vasodilatation may also explain the report by Murray and Paller (1986) of reduced nephrotoxicity with concomitant prazosin therapy. In an uncontrolled retrospective study, Feehally et al. (1987) found that a group of patients on cyclosporin and nifedipine had slightly lower serum creatinine levels than patients with comparable cyclosporin blood levels but not on nifedipine. Other drugs assessed experimentally include captopril and theophylline: neither affected nephrotoxicity (Gerkens and Smith, 1985). Prostaglandin E2 reduced nephrotoxicity and immunosuppression by cyclosporin in rats in experiments by Ryffel et al. (1986a). On the basis of kinetic studies the authors attributed these effects to diminished absorption of cyclosporin. Although Prostaglandin E2 is not a clinically important drug, prostaglandin inhibitors are. The non-steroidal antiinflammatory agents are common drugs with well documented nephrotoxic potential even in the absence of cyclosporin (van Rijthoven et al., 1986). 6.4.2. Exacerbation o f Nephrotoxicity All drugs known to be nephrotoxic in their own rights have been suspected of exacerbation of cyclosporin nephrotoxicity. These include amphotericin B, which appears to cause additive nephrotoxicity without altering cyclosporin blood levels (Kennedy et al., 1983). The same holds for melphalan (Morgernstern et al., 1982), nephrotoxic cephalosporins (Whiting et al., 1983) diuretics such as frusemide (Whiting et al., 1984), and aminoglycosides such as gentamicin (Burke and Whiting, 1986; Termeer et al., 1986). 6.5. DRUGSAFFECTINGCYCLOSPORINABSORPTIONAND DISTRIBUTION Assessment of those drugs likely to affect cyclosporin therapy depends on knowledge of the absorption, distribution and elimination of cyclosporin. These topics are discussed in more detail above under the relevant headings. Briefly, cyclosporin absorption is affected by drugs altering bowel motility and bile flow. Wadhwa et al. (1987b) quote an increase in bioavailability by 29% when metoclopramide was introduced, and thereby aspire to a major impact on the overall cost of cyclosporin therapy. Of more immediate practical importance is that prescription of metoclopramide for nausea may change a patient's cyclosporin dose from therapeutic to toxic. There is also the argument, not yet backed by clinical evidence, that drugs altering splanchnic blood flow may change cyclosporin absorption significantly. JPT 42/l--J

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Because cyclosporin in blood is so highly bound to lipoproteins, agents altering the lipid profile are likely to alter distribution of the drug. The clinical importance of this is not yet substantiated. 6.6. DRUGSAFFECTING CYCLOSPORIN METABOLISM 6.6.1. Introduction The impact on cyclosporin metabolism of drugs affecting liver blood flow is not yet defined. In contrast, drug interactions based on the cytochrome P450 enzyme system are extensively documented. Some of the experimental evidence is discussed above (Section 5.2.5). 6.6.2. Anticonvulsant Agents Anticonvulsant drugs induce cytochrome P450 enzymes, accelerating cyclosporin metabolism. Newer evidence in man backs up earlier work in rats (Cunningham et aL, 1984, 1985; Burke and Whiting, 1986; Schwass et al., 1986). Carstensen et aL (1986) showed in one bone marrow transplant recipient that the introduction of phenobarbitone was followed by a reduction in cyclosporin level to levels undetectable by RIA. Lele et al. (1985) showed the same change in a patient given carbamazepine. Burke and Rigby (1986) reported that a child on maintenance therapy of sodium valproate tolerated an unexpectedly high dose of cyclosporin with unexpectedly low blood levels, but wisely did not claim that the only possible explanation was induction of cytochrome P450[ A formal kinetic study by Freeman et al. (1984) reported increased cyclosporin clearance after phenytoin therapy in six normal males. 6.6.3. Antituberculous Agents Antituberculous therapy may also interact with cyclosporin. Rifampicin induces microsomal enzymes and accelerates cyclosporin metabolism. There are several reports of cyclosporin levels falling, and renal transplants lost through rejection, when in transplant patients given rifampicin (Langhoff and Madsen, 1983; Daniels et al., 1984; Allen et al., 1985; Cassidy et al., 1985; Coward et al., 1985). Although isoniazid was given in standard combination with rifampicin in these patients, the rapid fall in cyclosporin level, at times to the undetectable range, has been attributed to rifampicin. In fact, isoniazid is a weak, non-specific inhibitor of cytochrome P450 (Muakkassah et al., 1981). Coward et al. (1985) described one patient who was already on rifampicin and isoniazid at the time of renal transplantation when cyclosporin was started. Very low cyclosporin blood levels were achieved with standard doses of the drug until pyrazinamide was substituted for rifampicin, with isoniazid continued. Although pyrazinamide is hepatotoxic, it is not known to affect the cytochrome P450 system directly. Stopping rifampicin was followed by a rise in cyclosporin blood level. Daniels et aI. (1984) claimed that enzyme induction might persist for up to 3 weeks after rifampicin was stopped. The difficulties experienced in maintaining adequate immunosuppression with cyclosporin of patients on rifampicin have prompted advocates of immunosuppressive regimes without cyclosporin and antituberculous regimes without rifampicin. 6.6.4. Antifungal Agents Drugs which inhibit the production of cytochrome P450 inhibit cyclosporin metabolism and may lead to increased circulating cyclosporin levels. The best substantiated example is ketoconazole. Gumbleton et al. 0985) showed experimentally that ketoconazole inhibits cytochrome P450 production and eyclosporin metabolism. In a mouse model, Anderson

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et al. (1987) demonstrated potentiation by ketoconazole of cyclosporin immunosuppres-

sion and nephrotoxicity. Clinical findings in man have uniformly confirmed the report by Ferguson et al. (1982), which documented clearly in a renal transplant patient a rise in the cyclosporin level by HPLC corresponding to a course of ketoconazole. It is interesting that Daneshmend (1982) found no increase in antipyrine clearance in eight normal subjects given ketoconazole. There has been recent controversy on the interaction, or lack of it, between cyclosporin and itraconazole, an antifungal agent with some similarity to ketoconazole. Kwan et al. (1987a) and Trenk et al. (1987) both reported patients whose cyclosporin levels rose during itraconazole therapy. Novakova et al. (1987) found no significant differences between cyclosporin levels measured by RIA in 14 bone marrow transplant recipients when on and off prophylactic itraconazole therapy. Shaw et al. (1987) objected to the parallel drawn by Kwan et al. (1987a) between itraconazole and ketoconazole. Itraconazole had been regarded as free from interactions involving cytochrome P450 so any interaction with cyclosporin was unlikely to involve its metabolism. Antifungal agents which do not appear to interact with cyclosporin are fluocytosine (Trenk et al., 1987) and clotrimazole (Ptachcinski et al., 1986b). 6.6.5. S e x Hormones Oral contraceptive agents are weak inhibitors of cytochrome P450 (Orme et aL, 1983). Ross et al. (1986) and Deray et al. (1987) have published case reports showing raised cyclosporin levels in patients on norethisterone. The patient described by Ross et aL (1986) had a further increment in cyclosporin level while on danazole. Moiler and Ekelund (1985) described one patient who continued pre-existing methyltestosterone treatment after starting cyclosporin. Not only were cyclosporin blood levels unusually high, but the elimination half life of cyclosporin was four days. 6.6.6. H2-Antagonists Another inhibitor of cytochrome P450 is cimetidine. Knodell et al. (1982) demonstrated binding of cimetidine to cytochrome P450 in both rats and man. Burke and Whiting (1986) confirmed enzyme inhibition in rats but were unable to show a consequent rise in cyclosporin levels. Schwass et al. (1986) found that cimetidine did not worsen cyclosporin nephrotoxicity in rats. These undramatic reports are echoed in man. Jarowenko et al. (1986) reviewed patients given cyclosporin and H2-antagonists. In seven renal allograft recipients, there was a significant rise in serum creatinine level after treatment with cimetidine or ranitidine, but in two patients studied separately cyclosporin kinetics appeared unaltered by H2-antagonist. No change in serum creatinine level was noted in the one patient in whom ranitidine was substituted for cimetidine. Because ranitidine does not bind to cytochrome P450, ranitidine is the H2-antagonist usually chosen for the patient on cyclosporin. Yet clinical evidence to support this practice remains inconclusive. 6.6.7. Erythromycin The interaction between erythromycin and cytochrome P450 has already been described (Section 5.2.5). Its effect is to decrease cyclosporin metabolism and increase circulating drug levels. Ptachcinski et aL (1985a) reported a patient in whom a course of erythromycin was associated with rising cyclosporin levels by HPLC. Since then there have been numerous corroborating reports, with rise and fall in cyclospodn levels corresponding to beginning and end of erythromycin therapy (Murray et al., 1987). Pharmacokinetic studies in man record clearly the interaction between cyclospodn and erythromycin. In five patients Hourmant et al. (1985) found that the ratio of cyclosporin blood levels obtained by RIA:HPLC remained constant during the course of ery-

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thromycin. Freeman et al. (1986) gave 10 normal males an oral dose of cyclosporin before and after a week's course of erythromycin. Measuring cyclosporin blood levels by both RIA and HPLC they found a rise in the peak concentration of cyclosporin achieved, and a reduction in the cyclosporin clearance. Vereerstraeten et al. (1987) found, in a study of eight haemodialysis patients, that the peak cyclosporin level, measured by RIA after an oral dose, was not significantly different with from without concomitant erythromycin therapy. Clearance of cyclosporin was however slower during the phase of treatment with erythromycin. Vereerstraeten et al. (1987) concluded that the likely explanation was reduced hepatic turnover of cyclosporin in the presence of erythromycin. Josamycin, a macrolide like erythromycin, may have a similar interaction with cyclosporin, as reported by Kreft-Jais et al. (1987). 6.6.8. Calcium Antagonists Diltiazem competes with cyclosporin for available cytochrome P450, leading to a rise in the cyclosporin level (Pochet and Pirson, 1986; Grino et al., 1986). Neumayer and Wagner (1986) suggested that the cost of cyclosporin therapy could be reduced if diltiazem were used to increase the level obtained for a given dose. Of the other common calcium antagonists, verapamil has been reported to increase cyclosporin levels (Lindholm and Henricsson, 1987). Bourbigot et al. (1986) found the same in a patient on nicardipine. There are no similar case reports for nifedipine. 6.7. INTERACTIONBETWEENCYCLOSPORINAND PREDNISOLONE

There are also drugs for whom the findings are disputed and the mechanisms uncertain, but which may alter cyclosporin metabolism. The most important of these clinically is prednisolone (or prednisone). Its importance relates to its widespread use, in combination with cyclosporin, for immunosuppressive therapy. Not only is the combination used as maintenance therapy, but additional large boluses of steroid are given for treatment of acute rejection in organ transplantation, and for induction of remission in autoimmune disease. In 22 of 33 patients studied by Klintmalm and Sawe (1984), cyclosporin concentrations measured by RIA increased after the administration of high dose methylprednisolone for graft rejection. In contrast, Ptachcinski et al. (1986b) reported increased cyclosporin clearance in seven patients receiving high dose steroids compared to when they were receiving lower, maintenance doses. Ptachcinski et al. (1986b) also suggested that patients on long-term steroids might clear cyclosporin faster than patients on immunosuppressive regimes not including steroids. Cyclosporin was reported to inhibit prednisolone metabolism (Ost et al., 1985; Langhoff et al., 1985). This was repudiated by Frey et al. (1987), who found no evidence in a study of 50 renal transplant recipients that cyclosporin affects prednisolone availability or clearance. Clinical experience suggests that there is no need to alter prednisolone or cyclosporin doses to atone for the presence of the other, although adequate immunosuppression may be achieved with lower doses of cyclosporin if it is combined with prednisolone (ForweU et al., 1987). 6.8. INTERACTIONBETWEENCYCLOSPORINAND TRIMETHOPRIM/SULPHONAMIDES There have been mixed reports of interaction between cyclosporin and the combination of trimethoprim and a sulphonamide. On the one hand, Jones et al. (1986) found that intravenous sulphadimidine, added to existing trimethoprim therapy, led to precipitate falls in cyclosporin levels in five patients. On the other hand, Thompson et al. (1983) found no change in cyclosporin levels, but increased serum creatinine levels when five patients on cyclosporin were given trimethoprim or cotrimoxazole. Trimethoprim alone may raise the serum creatinine level by competitive inhibition of tubular creatinine secretion (Wadhwa et al., 1987b). Ringden et al. (1984) reviewed cohorts

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of renal and bone marrow transplant recipients on cyclosporin or azathioprine. When cotrimoxazole was added, a rising serum creatinine level was noted in a significantly greater proportion of patients treated with cyclosporin than with azathioprine. A further twist was provided by Kimmel et al. (1985). In their HPLC assay system for cyclosporin, sulphamethoxazole gave an identical 'peak', so measurement of cyclosporin level in the presence of sulphamethoxazole led to an artefactually high result. Pneumocystis pneumonia is the only compelling indication for cotrimoxazole in the cyclosporin-treated patient, and obsessive monitoring of cyclosporin and creatinine levels is necessary.

6.9. OTHERDRUGS AFFECTEDBY CYCLOSPORIN Dorian et al. (1987) concentrated on digoxin, rather than cyclosporin kinetics when studying the interaction between the drugs in two patients prior to heart transplantation. The volume of distribution and plasma clearance of digoxin fell with cyclosporin by around 70% and 50% respectively. The authors thought that the magnitude of these changes was too great to be explained solely by reduced renal blood flow caused by cyclosporin, and concluded that digitoxicity might be precipitated by cyclosporin. Slater et al. (1986) found that cyclosporin corrects daunorubicin resistance in Ehrlich ascites carcinoma in mice. This observation was attributed to an ill-defined action of cyclosporin on the cell membrane, rather than an interaction with daunorubicin itself. There are no reports in man of interaction between cyclosporin and daunorubicin. A notable omission from the list of reported clinical interactions is warfarin, which also uses cytochrome P450. A drug commonly used in immunosuppressed patients is the antiviral agent acyclovir. Johnson et al. (1987) found no evidence of interaction between acyclovir and cyclosporin. Cyclosporin therefore is a drug with many reported and potential interactions. Variability between patients is considerable. Changes in concomitant medication should be accompanied by careful assessment of renal function and cyclosporin levels.

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COWARD, R. A., RAFTERY,A. T. and BROWN,C. B. (1985) Cyclosporin and antituberculous therapy. Lancet I: 1342-1343. CUNNINGrO~M,C., BURKE,M. D., WnEATL~Y,D. N., "IMoMSON,A. W., SIre'SON,J. G. and WmTXNG,P. H. (1985) Amelioration of cyclosporin-induced nephrotoxicity in rats by induction of hepatic drug metabolism. Biochem. Pharmac. 34: 573-578. CUNNINGHAM,C., GAVIN,M. P., WHITING,P. H., BURKE,M. D., MACINTYRE,F., THOMSON,A. W. and SI~tPSON, J. G. (1984) Serum cyclosporin levels, hepatic drug metabolism and renal tubulotoxicity. Biochem Pharmac. 33: 2857-2861. DANAN,G., DESCATOIRE,V. and PRESSAYRE,D. (1981) Self-induction by erythromycin of its own transformation into a metabolite forming an inactive complex with reduced cytochrome P450. J. Pharmac. exp. Ther. 218: 509-514. DANESHMEND,T. K. (1982) Ketoconazole--cyclosporin interaction. Lancet 2: 1342-1343. DANIELS,N. J., DOVER,J. S. and SCHACHTER,R. K. (1984) Interaction between cyclosporin and rifampicin. Lancet 2: 639. 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(1985) Cyclosporin, blood-brain barrier, and multiple sclerosis. Lancet 2: 889-890. FEEHALLY,J., WALLS,J., MISTRY,N., HORSBURGH,T., TAYLOR,J., VEITCH,P. S. and BELL,P. R. F. (1987) Does nifedipine ameliorate cyclosporin A nephrotoxicity? Br. Med. J. 295: 310. FEROUSON,R. M., SUTHERLAND,D. E. R., SIMMONS,R. L. and NAJARIAN,J. S. (1982) Ketoeonazole, cyclosporin metabolism, and renal transplantation. Lancet 2: 882-883. FLECHNER, S. M., KATZ, A. R., ROGERS,A. J., VAN BUREN, C. and KAHAN,B. D. (1985) The presence of cyclosporine in body tissues and fluids during pregnancy. Am. J. Kidney Dis. 5: 60-63. FOLLATH, F., WENK, M., VOZEH,S., THIEL, G., BRUNNER,F., LOERTSCHER,R., LEMAIRE,M., NUSSBAUMER,W. and WOOD, A. (1983) Intravenous cyclosporine kinetics in renal failure. Clin. Pharmac, Ther. 34: 638-643. FORWELL,M. A., BRADLEY,J. A., BRIGGS,J. D., BROWN,M. W., JUNOR,B. J. R., MACPHERSON,S. G. and WATSON, M. A. (1987) Low-dose cyclosporine or azathioprine one year after renal transplantation. Transplant Proc. 19: 1858-1859. FREEMAN,D. J., LAUPACIS,A., KEOWN,P. A., STILLER,C. R. and CARRUTHERS,S. G. (1984) Evaluation of cyclosporin-phenytoin interaction with observations on cyclosporin metabolites. Br. J. Clin. Pharmac. 18: 887-893. FREEMAN,n. J., MAR.TELL,R., CARRUTHERS,S. G. and KEOWN,P. A. (1986) The effect of erythromycin on the pharmacokinetics of cyclosporine. Clin. Pharmac. Ther. 39: 193. FREY, F. J., SCHNETZER,A., HORBER,F. F. and FREY,B. i . (1987) Evidence that cyclosporine does not affect the metabolism of prednisolone after renal transplantation. Transplantation 43: 494-498. GERKENS,J. F. and SMITH,A. J. (1985) Effect of captopril and theophylline treatment on cyclosporine-induced nephrotoxicity in rats. Transplantation 40: 213-214. GRAMSTAD,L., GJERDLOW,J. A., HYSINO,E. S. and RUOSTAD,H. E. (1986) Interaction of cyclosporin and its solvent, cremophor, with atracurium and vecuronium. Br. J. Anaesth. 58:1149-1155. GREVEL,J., NUESCH,E., AmSCH,E. and KUTZ, K. (1986) Pharmacokinetics of oral cyclosporin A (Sandimmun) in healthy subjects. Eur. J. Clin. Pharmac. 31: 211-216. GRIDELLI,B., SCANLON,L., PELLICCI,R., LAPOINTE,R., DEWOLL,A., SELTMAN,H., DIVEN,W., SHAW,B., STARZL, T. and SANGHVI,A. (1986) Cyclosporine metabolism and pharmacokinetics following intravenous and oral administration in the dog. Transplantation 41: 388-391. GRINO,J. M., SABATE,I., CASTELAO,A. M. and ALSINA,J. (1986) Influence of diltiazem on cyclosporin clearance. Lancet 1: 1387. GLrMBLETON,M., BROWN,J. E., HAWKESWORTH,G. and WHITING,P. H. (1985) The possible relationship between hepatic drug metabolism and ketoconazele enhancement of cyclosporine nephrotoxicity. Transplantation 40: 454-455. HAMILTON,G., MUrILBACrlER,F., ROTH, E., WOLF, I., Pmx, F., HAVEL,M., LACKOVICS,A., SCHINDLER,J. and WOLOSCZUK,W. (1987) Comparison of cyclosporin A dosage and metabolism in liver and heart transplant recipients. Transplant Proc. 19: 1706-1708. HAggis, K. P., RUSSELL,G. I., PARVIN,S. D., VEITCH, P. S. and WALLS,J. (1986) Alterations in lipid and carbohydrate metabolism attributable to eyclosporin A in renal transplantation. Br. Med. J. 292: 16. HEINgICrtS, D. A., MAgTELL, R., STmLF.g,C. R., FREEMAN,D. and CAgRtrrrmgs, G. (1987) The effects of co-dergocrine on cyclosporin A pharmacokinetics and pharmacodynamics. Br. J. Clin. Pharmac. 24: 117-118. HENNY, F. C., KI_EINBLOESEM,C. H., MOOLENAAR,A. J., PAUL,L. C., BREIMER,D. D. and VANES, L. A. (1985) Pharmacokinetics and nephrotoxicity of cyclosporine in renal transplant recipients. Transplantation 40: 261-265. HOLT, D. W. (1986) Methodology of cyclosporin monitoring: current status and applications. In: Cyclosporin: Issues o f Today, pp. 3-11, Medical Education Services, Oxford.

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HOUtMAWr,M., LE BIGOT,J. F., VER~LLET,L., SAGNW.Z,G., ~.MI, J. P. and SOULILLOU,J. P. (1985) Coadministration of erythromycin results in an increase of blood cyclosporine to toxic levels. Transplant Proe. 17: 2723-2727. JAgOWENKO,M. V., VANBUREN,C. T., KRAMER,W. G., LORJ~R,M. I., F L E ~ , S. M. and KAHAN,B. D. (1986) Ranitidine, cimetidine and the cyclosporine-treated recipient. Transplantation 42: 311-312. JOHNSON, P. C., KUMOR,K., WELSH,M. S., WOO, J. and KAHAN,B. D. (1987) Effects of coadministration of cyclosporine and acyclovir on renal function of renal allograft recipients. Transplantation 44: 329-331. JOHNSTON,A., MARSDEN,J. T., HLA, K. K., HENRY,J. A. and HOLT,D. W. (1986) The effect of vehicle on the oral absorption of cyclosporin. Br. J. Clin. Pharmac. 21: 331-333. JONES, D. K., HAKIM,M., WALLWORK,J., HIOENBOTTAM,T. W. and WroTE, D. J. G. (1986) Serious interaction between cyclosporin A and sulphadimidine. Br. Med. J. 292: 728-729. KAHAN, B. D. (1985) Individualization of cyclosporine therapy using pharmacokinetic and pharmacodynamic parameters. Transplantation 40: 457-476. KAHAN, B. D., KRAMER,W. G., WlDEMAN,C., FLECHNER,S. M., LOanER, M. I. and VAN BUREN,C. T. (1986) Demographic factors affecting the pharmacokinetics of cyclosporine estimated by radioimmunoassay. Transplantation 41: 459-464. KENNEDY,M. S., DEEG,H. J., SIEGEL,M., CROWLEY,J. J., STOP,e, R. and THOMAS,E. D. (1983) Acute renal toxicity with combined use of amphotericin B and cyclosporine after marrow transplantation. Transplantation 35: 211-215. IO~owN, P. A., STILLER,C. R., ULAN, R. A., SINCLAIR,N. R., WALL,W. J., CARRUTHERS,G. and HOWSON,W. (1981) Immunological and pharmacological monitoring in the clinical use of cyclosporin A. Lancet 1: 68(~689. K I ~ L , P. L., PmLIPS,T. M., KRA~,mR,N. C. and THOMPSON,A. M. (1985) In vitro and /n vivo interaction of sulfamethoxazole (SMX) with cyclosporin A (CsA) measurement by high pressure liquid chromatography (HPLC). Kidney Int. 27: 343. KLINTMALM,G. and S^wE, J. (1984) High dose methylprednisolone increases plasma cyclosporin levels in renal transplant recipients. Lancet I: 731. KNODELL,R. G., HOLTZMAN,J. L., CRANKSHAW,D. L., STEELE,N. M. and STANLEY,L. N. (1982) Drug metabolism by rat and human hepatic microsomes in response to interaction with H2-receptor antagonists. Gastroenterology 82: 84-96. KREFT-JAIS, C., BILLAUD, E. M., GAUDRY, C. and BEDROSSIAN,J. (1987) Effect of josamycin on plasma cyclosporine levels. Eur. J. Clin. Pharmae. 32: 327-328. KWAN, J. T. C., FOXALL,P. J. D., DAVIDSON,D. G. C., BENDING,M. R. and EISINOER,A. J. (1987a) Interaction of cyclosporin and itraconazole. Lancet 2: 282. KWAN, J. T. C., FOXALL,P. J. D., TOWNEND,J. N., THICK,M. G., BENDING,M. R. and EISINGER,A. J. (1987b) Therapeutic range of cyclosporin in renal transplant patients by specific monoclonal radioimmunoassay. Lancet 2: 962-963. LANOHOFF,E. and MADSEN,S. (1983) Rapid metabolism of cyclosporin and prednisone in kidney transplant patient receiving tuberculostatic treatment. Lancet 2: 1031. LANGHOFF,E., MADSEN,S., FLACHS,H., OLGAARD,K., LADEFOGED,J. and HVlDBERG,E. F. (1985) Inhibition of prednisolone metabolism by cyclosporine in kidney-transplanted patients. Transplantation 39: 107-109. LARREY,D., FUNCK-BRENTANO,C., BREIL,P., VITAUX,J., TI~ODORE,C., BABANY,G. and PRESSAYS~,D. (1983) Effects of erythromycin on hepatic drug-metabolizing enzymes in humans. Biochem. Pharmac. 32: 1063-1068. LELE,P., PETERSON,P., YANG,S., JARRELL,B. and BURKE,J. F. (1985) Cyclosporine and tegretol--another drug interaction. Kidney Int. 27: 344. LEMAIRE,M. and TILLEMENT,J. P. (1982) Role of lipoproteins and erythrocytes in the /n vitro binding and distribution of cyclosporin A in the blood. J. Pharm. Pharmac. 34: 715-718. LINDHOLM,A. and HENRICSSON,S. (1987) Verapamil inhibits cyclosporin metabolism. Lancet 1: 1262-1263. LINDHOLM,A., RINGDEN,O. and LOr,~QVlST,B. (1987) The role of cyclosporin dosage and plasma levels in efficacy and toxicity in bone marrow transplant recipients. Transplantation 43: 680-684. LIU, T., SUTHERLAND,D. E. R., FIELD,J. and NAJSJUAN,J. S. (1985) Paradoxic effects of propranolol given with azathioprine or cyclosporine to rat heart and islet allograft recipients. Transplant Proc. 17: 240-243. MAURER,G., LOOSLI,H. R., SCHREIER,E. and KELLER,B. (1984) Disposition of cyclosporin in several animal species and man: I Structural elucidation of its metabolites. Drug Metab. Dispos. 12: 120-126. MCMILLAN,M. A., BAUMGARTEN,W. K., SCHAEFER,H. C., MITCHNICK,E., FUORTES,M., HOLMAN,M. J. and TESl, R. J. (1987) The effect of verapamil on cellular uptake, organ distribution, and pharmacology of cyclosporine. Transplantation 44: 395-401. MCMILLAN, M. A., TF~I, R. J., B^UMGARTEN,W. B., JAFFE, B. M. and WAIT, R. B. (1985) Potentiation of cyclosporine by verapamil/n vitro. 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154

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M. A. McMu.t,AN

156

APPENDIX. SELECTED REPORTS OF DRUG WITH CYCLOSPORIN

Drug Amphotericin B Atracurium Carbamazepine Cephalosporins Cimetidine Clotrimazole Codergocrine Cotrimoxazole Danazol Daunorubicin Diltiazem Digoxin Erythromycin

Frusemide Gentamicin Indomethacin Isoniazid Itraconazole

Iosamycin Ketoconazole

Reference Kennedy et al. (1983) Gramstad et al. ( 1 9 8 6 ) Lele et al. (1985) Whiting et al. (1983) Schwass et al. (1986) Burke and Whiting ( 1 9 8 6 ) Jarowenko et al. (1986) Ptachcinski et al. ( 1 9 8 6 b ) Heinrichs et al. (1987) Thompson et al. ( 1 9 8 3 ) Ringden et aL (1984) Ross et al. (1986) Slater et aL (1986) Pochet and Pirson (1986) Grino et al. (1986) Neumayer and Wagner (1986) Dorian et al. (1987) Ptachcinski et al. (1985a) Hourmant et al. (1985) Freeman et al. (1986) Vereerstraeten et al. ( 1 9 8 7 ) Murray et al. (1987 Whiting et al. (1984) Burke and Whiting (1986) Termeer et al. (1986) Ptachcinski et al. (1986b) Langhoff and Madsen (1983) Kwan et al. (1987a) Trenk et al. (1987) Novakova et al. ( 1 9 8 7 ) Shaw et al. (1987) Kreft-Jais et al. (1987) Morgenstem et al. (1982) Gumbleton et al. 0985) Ferguson et aL (1982) Burke and Whiting (1986) Anderson et al. (1987)

INTERACTIONS

Drug Melphalan Metoclopramide Methyltestosterone Nicardipine Nifedipine Norethisterone Non-steroidal antiinflammatory drugs Phenobarbitone

Phenytoin Prazosin Prednisolone Prednisone

Propranolol Ranitidine Rifampicin

Sodium valproate Sulphadimidine Sulphamethoxazole Trimethoprim Verapamil

Vercuronium

Reference Morgenstern et al. (1982) Wadhwa et al. (1987a,b) Moiler and Ekehind (1985) Bourbigot et al. (1986) Feehally et al. (1987) Ross et al. (1986) Deray et aL (1987) van Rijthoven et al. (1986) Cunningham et al. (1985) Carstensen et al. (1986) Schwass et al. (1986) Burke and Whiting (1986) Freeman et al. (1984) Murray and Pailer (1986) Langhoff and Madsen (1983) Langhoff et al. (1985) Klintmalm and Sawe (1984) Ost et al. (1985) Frey et aL (1987) Liu et al. (1985) Jarowenko et aL (1986) Langhoff and Madsen (1983) Daniels et aL (1984) Allen et al. (1985) Cassidy et al. (1985) Coward et aL (1985) Burke and Rigby (1986) Jones et aL (1986) Kimmel et aL (1985) Thompson et al. (1983) Ringden et al. (1984) McMillen et aL (1985) McMillen et al. (1987) Lindholm and Henricsson (1987) Gramstad et al. (1986)