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Drug interactions at excretory mechanisms
Pharmac. Ther. Vol. 15. pp. 69 to 78, 1981 Printed in Great Britain. All rights reserved
0163o7258 81 01(}069-10505.00 0 Copyright © 1981 Pergamon Press Lid
Specialist Subject Editors: P. F. D'ARcv and J. P. GRIFFIN
DRUG
INTERACTIONS
AT EXCRETORY
MECHANISMS
L. OFFERHAUS Netherlands Committee on the Evaluation o]" Medicines, P.O. Box 5811, 2280 H V Rijswijk (ZH), The Netherlands
1. INTRODUCTION Drugs and drug metabolites are excreted through active and passive mechanisms by the kidney and the biliary tract, and to a minor and variable extent by the lungs, through the skin, and in saliva, milk and sweat. Whereas the hepatobiliary route of excretion is only important for a limited number of drugs (e.g. ampicillin, digitoxin, glutethimide, phenprocoumon), which in addition may undergo extensive enterohepatic recirculation after reabsorption through the intestinal wall, most drugs and drug metabolites are excreted mainly by the kidney. Excretion, at least at plasma concentrations within the therapeutic range, will occur at a rate proportional to the amount of drug present in the body, either by passive glomerular filtration of the fraction of the drug not bound to plasma proteins, or by active tubular secretion, using two still poorly defined carrier mechanisms, one for weak acids (Despopoulos, 1965), and another for weak bases (Peters, 1960). Weak acids are excreted more rapidly in alkaline urine, weak bases more rapidly in acid urine. The main site of the tubular secretion of drugs is the proximal convoluted tubule. Nonionized, and therefore more lipid-soluble, drug will be passively and rapidly reabsorbed, whereas the ionized drug fraction will be excreted. As the relative proportion of ionized and nonionized drug, depending on the p K a of the drug, is determined by the pH of the tubular urine, any change of the pH will profoundly influence the reabsorption process. Moreover, the amount of drug reabsorbed by the tubular epithelium increases as the iso-osmotic reabsorption of water increases during the passage of urine down the nephron, and the relative concentration of the drug in the tubular urine rises. Drug interactions in the kidney are mainly influenced by competition (both during active secretion of the drug and during passive reabsorption) for the pump mechanism in the tubular cells, acids competing with acids and bases with bases (Weiner and Mudge, 1964); by changes in the luminal pH, and by changes in the urinary flow rate which will influence both the process of reabsorption and the pH (Bennett et al., 1979). Drug interactions can therefore be expected if drugs which are mainly secreted by the proximal convoluted tubule (Table 1) are used simultaneously. Moreover, drugs which depress glomerular filtration rate (e.g. many anti-inflammatory and antihypertensive drugs, triamterene) or impair the tubular reabsorption of drug molecules which are predominantly excreted by glomerular filtration, and partially reabsorbed in the tubules (e.g. lithium-, bromide- and fluoride-ions, digoxin) may change the renal clearance of such drugs. No obvious examples of drug interaction during biliary excretion due to competition of drugs for hepatobiliary excretion mechanisms are known. However, the excretion of drugs which undergo recirculation after intestinal reabsorption may be enhanced by the simultaneous administration of anion exchange resins, e.g. cholestyramine and colestipol. Despite the many hundreds of possible drug interactions during the excretory phase described in the pharmacological and pharmaceutical literature, many of them anecdotal and poorly documented, only very few of them are clinically important. The problem of drug interactions (particularly those occurring during excretion) has been "vastly overes69
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L. OFFERHAUS TABLE 1. Drugs Excreted by the Proximal Convoluted "luhule Weak Acids Diuretics Acetazolamide Ethacrynic acid Frusemide Thiazide diuretics Spironolactone Uricosuric drugs Benziodarone Probenecid Sulfinpyrazone Anti-inflammatory drugs Acetylsalicylic acid Indomethacin Oxyphenbutazone Phenylbutazone Salicylic acid Others p-Aminosalicylic acid (PAS) Chlorpropamide Clofibrate (metabolite) Fusidic acid Methotrexate Nalidixic acid Penicillins Phenobarbital Sulfonamides Sulfonic acids (Dapsone)
Weak Bases Tricyclic antidepressants Amitryptiline Desmethylimipramine Imipramine Nortryptiline Others Amphetamines Chloroquine Dopamine Fenfluramine Histamine Morphine Pethidine Procaine Quinine Quinidine Thiamine
Adapted from: Reidenberg (1971), Wade and Beeley (1976), Bennett et al. (1979) and Griffin and D'Arcy (1979).
timated and its applicability exaggerated beyond all reason" (Koch-Weser and Greenblatt, 1977), and particularly interactions between anti-inflammatory drugs and diuretics have, in a sample of 10,518 hospitalized patients, not been shown to cause any clinical problems (May et al., 1977). Any discussion of drug interactions during the excretory phase should therefore be confined to those interactions which have been conclusively demonstrated in man and which are clinically relevant, i.e. those which influence the effectiveness or safety of drug therapy. Even so, drug interactions within this category are rarely dangerous. From the clinician's point of view the most important drugs known to cause this type of interaction belong to the following categories: (a) the loop-diuretics frusemide (furosemide) and ethacrynic acid; (b) the uricosuric drug probenecid; and (c) quinidine, which recently has been shown to reduce the renal excretion of digoxin. Other weakly acid drugs will only occasionally cause such interactions. 2. I N T E R A C T I O N S WITH A C I D D R U G S 2.1. FRUSEMIDE AND DRUG INTERACTIONS DURING THE EXCRETORY PHASE
Frusemide is a weakly acid derivative of anthranilic acid. 90~o of the absorbed fraction is eliminated by the kidney in unchanged form (mainly by proximal tubular secretion), and the remaining 10~o in the bile (Cutler et al., 1974; Kelly et al., 1974). On theoretical grounds one could expect probenecid to impair the diuretic effect of frusemide, because frusemide has to be secreted into the lumen of the proximal tubule in order to exert its diuretic effect (Odlind and Beermann, 1980), and probenecid could prevent frusemide access to the tubular lumen by blocking its cellular transport (Benet, 1979). The results obtained in studies in which the two drugs were given simultaneously (Honari et al., t977; Homeida et al., 1977; Brater, 1978; Andreasen et al., 1980) have, however, been extremely complex. Though pretreatment with probenecid decreases both the renal and the extrarenal clearance of frusemide, and increases its half-life by 540/o it does not alter
Drug interactions at excretory mechanisms
71
the ratio between urinary frusemide and urinary sodium. The amount of unchanged drug reaching the tubular lumen remains unchanged, and so does the total diuretic response. Because probenecid displaces frusemide from protein binding sites, the relatively higher fraction of unbound frusemide reaching the inside of the tubular lumen probably compensates for the reduction of the frusemide elimination (Smith et al., 1980). Both indomethacin (FriSlich et al., 1976; Benet, 1979) and acetylsalicylic acid (Bartoli et al., 1980) attenuate frusemide diuresis. Indomethacin pretreatinent reduces frusemide excretion by 18~o, urinary output by 23°.0 and sodium excretion by 28~o. Though the effect was attributed to prostaglandin-synthetase inhibition by indomethacin, Benet (1979) showed that indomethacin indeed inhibits frusemide elimination, but that the increased plasma levels of frusemide caused the amount of drug excreted unchanged in the urine to decrease only slightly. He therefore concluded that, though a pharmacokinetic interaction could be demonstrated, this could not explain the pharmacodynamic adverse effect of indomethacin on frusemide diuresis. In contrast to Benet's findings Bartoli et al. (1980) observed that a high i.v. dose (1.5 g) of acetylsalicylic acid reduced frusemide-induced sodium excretion by 29?o and urinary flow rate by 25°/o, and that those changes closely correlated with a decrease of the urinary clearance of frusemide. Moreover, acetylsalicylic acid alone did not change water and sodium output. These observations make a competition of frusemide and acetylsalicylic acid for the same carrier mechanism in the tubular cell likely. Frusemide may enhance the ototoxicity of aminoglycoside antibiotics (American Pharmaceutical Association, 1976), and the nephrotoxicity of cephaloridine (Dodds and Foord, 1970), particularly in patients with renal insufficiency. The mechanism of this interaction is poorly understood, but the increased toxicity is probably caused by the additive toxic properties of both drugs. Pharmacokinetic studies have not been done. Though frusemide-induced hypokalaemia may potentiate both the efficacy and the toxicity of cardiac glycosides, frusemide does not alter digoxin elimination or steady-state serum digoxin levels (Brown et al., 1976). Theoretically chronic treatment with frusemide might decrease lithium clearance, particularly in combination with dietary sodium restriction. However, though most reference texts on drug interactions mention this possibility, no cases of frusemide-induced lithium toxicity have been reported. Thiazide diuretics may raise serum lithium levels up to three times the normal value in lithium-induced nephrogenic diabetes insipidus (Rosenbaum et al., 1979), and the risk of combining these drugs is not inconsiderable (Jefferson, 1980), though the drugs may be combined if the serum lithium level is closely monitored (Chambers et al., 1977). However, the site of this interaction being the distal renal tubule, the same may not hold true for frusemide, which has its main site of action in the proximal tubule and Henle's loop (Thomsen and Schou, 1968). 2.2. ETHACRYNIC ACID AND DRUG INTERACTIONS DURING THE EXCRETORY PHASE In contrast to frusemide, interactions with ethacrynic acid have scarcely been studied. Hearing loss may occur if ethacrynic acid is combined with aminoglycoside antibiotics (i.e. kanamycin, gentamicin, neomycin, streptomycin and tobramycin), particularly in patients with renal insufficiency (American Pharmaceutical Association, 1978). The mechanism of this interaction is unknown. A pharmacokinetic interaction within the kidney has not been excluded, but concrete data are not available. 2.3. SPIRONOLACTONE AND DRUG INTERACTIONS DURING THE EXCRETORY PHASE 600 mg of acetylsalicylic acid given orally reduces the natriuretic effects of spironolactone in a single-dose experiment in normal subjects (Tweeddale and Ogilvie, 1973) by 13-24~o, depending on the dose of spironolactone, and by 30?o during chronic treatment with 25 mg spironolactone q.i.d. This observation has been confirmed by Ramsay et al. (1976). Acetylsalicylic acid probably blocks the carrier-mediated secretion of the principal
72
L. OFFERHAUS
spironolactone metabolite canrenone in the proximal convoluted tubule, thus blunting its diuretic effect. Spironolactone blocks the tubular secretion of digoxin (Steiness, 1974) but this, being only a minor elimination pathway of the drug, does not fully account for the raised serum levels of digoxin found during combined treatment with digoxin and spironolactone, because spironolactone reduces the volume of the deep digoxin compartment (Waldorff et al., 1978), and may compete for digoxin receptor sites. Digoxin dose should be reduced by approximately 30% in patients receiving spironolactone treatment. On the other hand, data on the well-known interaction between spironolactone and digitoxin seem to be conflicting because both a prolongation (Carruthers and Dujovne, 19801 and a reduction (Wirth et al., 1976) in digitoxin half-life during spironolactone treatment have been reported; no clinical data on enhanced digitoxin toxicity in spironolactone-treated patients are available. Many earlier studies have been confounded by the interference of the metabolite canrenone with the radioimmunoassay of cardiac glycosides using unspecific methods (Lichey et al., 1977). 2.4. PROBENEC1D AND DRUG INTERACTIONS DURING THE EXCRETORY PHASE Probenecid, a benzoic acid derivative, owes its uricosuric action to its ability to block the carrier-mediated transport of many weak organic acids from and into the tubular lumen. It promotes the excretion of uric acid by blocking its reabsorption through the tubular epithelium, and it blocks the tubular excretion of many acid drugs, e.g. penicillins, cephalosporins, dapsone, rifampicin, nitrofurantoin, sulphonamides, methotrexatc, salicylates (including p-aminosalicylic acid), some oral antidiabetics (chlorpropamide and acetohexamide), thiazide diuretics, and indomethacin. Most reports of these interactions are anecdotal and poorly documented, or clinically irrelevant. Prospective clinical pharmacological studies are almost non-existent, Very few of these interactions carry any risk in the clinical situation, either because the interacting drug has a wide margin of safety, or because indications to combine the drugs simply do not exist. Salicylates should certainly not be combined with probenecid, because they antagonise the uricosuric effect of probenecid (Hansten, 1976). On the other hand, probenecid is widely used to reduce the renal clearance of penicillins (particularly ampicillin, carbenicillin and methicillin) in order to obtain high plasma levels in severe infections, and in combination with cephalosporins (particularly cephalotin), though caution is necessary in patients with decreased renal function, because such high serum levels may cause ototoxicity. Furthermore, it might be used to enhance the clinical effect of indomethacin (Brooks et al., 1974) and to prolong the duration of action of this drug during the night. 2.5. OTHER WEAK ACIDS WHICH MIGHT CAUSE CLINICALLY IMPORTANT DRUG INTERACTIONS DURING THE EXCRETORY PHASE
Phenylbutazone and its principal metabolite oxyphenbutazone, as well as indomethacin, sulfinpyrazone and acetylsalicylic acid slow the renal excretion of penicillin (Kampmann et al., 1972, Brooks et al., 1974) and phenylbutazone potentiates the hypoglycaemic effect of acetohexamide (Field et al., 1967). Acetylsalicylic acid has been shown to compete with the tubular excretion of methotrexate (American Pharmaceutical Association, 1978), but definite clinical proof that acetylsalicylic acid increases the toxicity of methotrexate is lacking. Acetazolamide, being a carbonic anhydrase inhibitor, alkalises the urine, and so may counteract the urinary disinfectant properties of acidifying agents such as methenamine mandelate, -hippurate and mandelic acid, and it may reduce the renal clearance of quinidine by this mechanism (Gerhardt et al., 19691. 3. INTERACTIONS WITH BASIC DRUGS 3.1. QUINIDINE AND DRUG INTERACTIONS WITH CARDIAC GLYCOSIDES DURING THE EXCRETORY PHASE
An interaction between quinidine and digitalis has been suspected since the Dutch Austrian cardiologist, Wenckebach, 70 years ago stressed the extraordinary potency of
Drug interactions at excretory mechanisms
73
his antiarrhythmic combination pills containing a mixture of digitalis leaf powder, quinidine and strychnine. Already 50 years ago this combination was reported to be hazardous (Gold et al., 1932). The interaction has recently been rediscovered (Ejvinsson, 1978), and this report was followed by numerous other publications confirming that quinidine raises serum digoxin levels (Leahey et al., 1978; Hooymans and Merkus, 1978; Leahey et al., 1979; Burkle and Matzke, 1979; Reid and Meek, 1979; Holt et al., 1979; Leahey et al., 1980). Quinidine, on average, causes a twofold increase in serum digoxin concentration in approximately 90~o of all patients using this drug combination, though the interindividual variation seems to be considerable. The extent of the rise in serum digoxin is related to the quinidine dose. The mechanism of this interaction has been the subject of a number of studies, both in volunteers and in patients (Hager et al., 1979; Doering, 1979; Risler et al., 1979; Dahlqvist et al., 1980; Mungall et al., 1980; Schenck-Gustafsson and Dahlqvist, 1981). Two different mechanisms seem to be involved, because quinidine treatment causes both a decrease of the volume of distribution of digoxin by approximately 33~o and a decrease of the renal digoxin clearance varying from 33~o to 57~o without a statistically significant change in the glomerular filtration rate. Only in one study (Dahlqvist et al., 1980), a relatively high dose (1200mg daily) of a slow-release preparation of quinidine, given to patients with moderate impairment of renal function, effected a drop of 23~o in the glomerular filtration rate during quinidine treatment, but an even greater drop of 70~o in the renal digoxin clearance. It seems therefore that quinidine displaces digoxin from peripheral tissue binding sites (mainly located in striated muscle tissue) without affecting binding to cardiac receptors, and competes with digoxin for carrier-mediated excretion mechanisms in the proximal tubule. Both interaction mechanisms tend to elevate serum digoxin levels to an average of twice the normal steady-state levels, and often well within the toxic serum range. The mechanism for which the drugs compete in the kidney is saturable, because further increases in quinidine dosage lead to increased changes in the volume of distribution and increased serum levels of digoxin without further affecting renal digoxin clearance (Risler et al., 1980). The mechanism of the displacement interaction will be treated in another review article in this series (Rawlins and Routledge, 1982). The interaction between quinidine and digoxin is not just another pharmacokinetic curiosity, but it can be particularly hazardous and may manifest itself as cardiac arrhythmias and other typical symptoms of digitalis toxicity (Holt et al., 1979; Leahey et al., 1978, 1979). The quinidine isomer, quinine, seems to have a different effect on digoxin disposition (Wandell et al., 1980), because it increases half-life and serum digoxin levels, does not affect renal digoxin clearance, but does decrease non-renal (biliary) clearance of digoxin by an average of 55%. Though it has been claimed (Ochs et al., 1980) that quinidine does not change digitoxin kinetics in healthy volunteers, the results obtained by other groups have yielded conflicting results; Peters et al. (1980) reported a moderate (+32°/o) increase in serum digitoxin level and a similarly increased half-life, but no changes either in renal or extrarenal clearance of digitoxin; however, Fenster et al. (1980) found similar moderate changes, but in addition a small, but statistically significant, decrease in renal digitoxin clearance by 30% without changes in protein binding or volume of distribution of the drug. The mechanism of the quinidine-digitoxin interaction may therefore be different from that of the quinidine-digoxin interaction, and the clinical implications of these observations seem still obscure. Moreover, all three studies were done in healthy volunteers. Pharmacokinetic studies in patients have not yet been done, and cases of unexpected digitoxin toxicity in patients treated with the combination of quinidine and digitoxin have not yet been reported. 3.2. LITHIUM SALTS AND DRUG INTERACTIONS DURING THE EXCRETORY PHASE Lithium ions are filtered by the glomerulus, and approximately 8000 of the filtered amount is reabsorbed by the renal tubules. Lithium clearance is therefore approximately
Salicylates l ndomethacin Phenylbutazone Oxyphenbutazone Sulfinpyrazone Acetylsalicylic acid
Methotrexate Penicillins
Penicillins (ampicillin, Inhibition of tubular excretion of (2) carbenicillin, methicillin); cephalosporins, dapsone, rifampicin(?), nitrofurantoin, sulfonamides, methotrexate, salicylates, chlorpropamide, acetohexamide, indomethacin
Probenecid
Inhibition of tubular excretion of (2) Inhibition of tubular excretion of (2)
Inhibition of tubular excretion of (2)
Digoxin
Spironolactone
? Probably additive toxic action
Competition over tubular transport Displacement from protein binding sites Inhibition of tubular excretion of (1); depression of glomerular filtration rate by (2). Competition for tubular transport ? Probably additive toxic action ? Probably additive toxic action
Mechanism of Interaction
Aminoglycosides
Acetylsalicylic acid Aminoglycosides Cephaloridine
lndomethacin
Probenecid
Drug 2
Ethacrynic acid
Frusemide
Drug 1
Clinical Implications
Increased methotrexate toxicity Probably none
Increased serum concentrations of (2); increased toxicity; increased clinical effect in drugs with systemic activity; decreased efficacy in urinary tract infections,
Increased serum digoxin concentration
Increased risk of hearing loss
Decreased diuretic response Increased risk of hearing loss Increased risk of renal damage
Decreased diuretic response
None demonstrated
TABLE 2. Clinically Important Drug Interactions at Excretory Mechanisms
>
r-
Low Na+-intake: Increased toxicity High Na+-intake: Decreased efficacy Increased bone loss Decreased efficacy Decreased efficacy Increased toxicity Increased efficacy and/or toxicity of (2)
Competition over tubular reabsorption Same Increased urinary pH, increased lithium-clearance ? Increased tubular reabsorption of (2) Increased urinary pH
Sodium-ions
Calcium-ions Sodium bicarbonate "~ Acetazolamide J Aminophylline Thiazide diuretics
Amphetamines Quinidine Tetracyclines
Lithium
Sodium bicarbonate Antacids (high dose, long-term) Acetazolamide Thiazide diuretics
Digoxin
Quinine
Digitoxin
None demonstrated
Increased serum digoxin concentration and increased toxicity risk.
Not studied.
Higher quinidine serum concentrations, increased efficacy and toxicity.
Increased urinary pH
Inhibition of extrarenal excretion of (2).
Digoxin
Quinidine
Decreased efficacy in urinary tract infections.
Increased urinary pH
Displacement from tissue binding sites; inhibition of tubular excretion of (2) ? Inhibition of extrarenal excretion
Methenamine mandelate Mandelic acid Methenamine hippurate Quinidine
Acetazolamide
o
e.,.q-
76
L. OFFERHAUS
20°,o of that of creatinine, i.e. 15 30ml/min. Though Li + is only a small molecule (m.w. = 7) it is to a certain extent exchangeable with much larger cations such as Na t (m.w. = 23), Ca 2+ (m.w. = 40), and Mg 2+ (m.w. = 24). Sodium loading enhances lithium excretion, sodium deprivation promotes retention of lithium; it promotes renal Ca z +-loss and increases extracellular Mg 2+, and in vitro it has a K+-like action on (Na + + K+) ATPase. The clinical implications of the exchangeability of the Li+-ion may be lithiumintoxication on a low-sodium diet, and loss of bone density during long-term treatment (Glen, 1976). Renal lithium clearance will be enhanced by alkalinization of the urine (by sodium bicarbonate or acetazolamide), during urea-induced osmotic diuresis, and by concomitant administration of aminophylline (Thomsen and Schou, 1968). Though single doses of diuretics do not affect renal lithium clearance, long-term thiazide therapy reduces clearance by approximately 24~, independent of sodium intake (Petersen et al., 1974). Because indications for prescribing lithium and diuretics together may exist [e.g. lithium-induced nephrogenic diabetes insipidus (Rosenbaum et al., 1979), or the combination of endogenous depression and heart failure], lithium concentration should be particularly carefully monitored if these drugs are combined, and lithium dose should preferably be reduced by approximately 50~o. 4. DRUG INTERACTIONS DURING THE EXCRETORY PHASE CAUSED BY DRUG-INDUCED CHANGES IN URINARY pH The renal clearance of weak bases is pH-dependent, being low if the urine is alkaline, and high in the presence of acid urine. Drugs which increase urinary pH (e.g. sodium bicarbonate, long-term high-dose antacid therapy, acetazolamide, thiazide diuretics) may cause reduction of renal clearance and accumulation of certain weak bases such as quinidine, amphetamines and tetracyclines. This interaction has been used by professional cyclists who combined the use of amphetamines with high doses of sodium bicarbonate to enhance the stimulating effect and to reduce the chances of being caught out during urine doping checks (Offerhaus, 1973). Though this interaction has been thoroughly investigated (Beckett and Rowland, 1965), the declining use of these drugs in clinical medicine makes the interaction relatively unimportant. Theoretically quinidine disposition might be profoundly altered by changes in urinary pH (Gerhardt et al., 1969), but clinical problems due to interaction with acidifying or alkalizing drugs seem to be rare, because therapeutic doses of such drugs rarely change urinary pH outside its normal rather narrow limit of 4.6-8.0. 5. CONCLUSIONS Though some of the earliest reports on clinically relevant drug interactions concerned interactions due to tubular excretion mechanisms (e.g. probenecid-penicillin and quinidine-digoxin), and numerous others, most of them pharmacological curiosities, have since been discovered and described, the implications for the patient of this type of drug interaction are relatively few. With the sole exception of the quinidine-digoxin and the thiazide-lithium interaction they rarely cause important changes in drug elimination and disposition and they are only exceptionally the cause of iatrogenic illness. A synopsis of the clinically important drug interactions of this type is given in Table 2. The principal mechanism involved seems to be competition of weak bases on the one side and of weak acids on the other hand for their respective carrier-mediated active tubular transport mechanisms, i.e. excretion from serum into the tubular urine and reabsorption of filtered drug from tubular urine back into the blood stream. Because the involvement of tubular transport mechanisms in drug interactions can only be elucidated using sophisticated and complicated clinical pharmacological methods of investigation, it may well be possible that other examples of the same kind of interaction will be discovered in the future. Moreover, surprisingly little research has been done on the possible role of acid drug
Drug interactions at excretory mechanisms
77
m e t a b o l i t e s , w h i c h are k n o w n to c a u s e p r o t e i n b i n d i n g d i s p l a c e m e n t i n t e r a c t i o n s . M a n y w e a k l y a c i d d r u g s w h i c h are a l m o s t o r e n t i r e l y e x c r e t e d in u n c h a n g e d f o r m by t h e k i d n e y m a y p o t e n t i a l l y c a u s e s u c h i n t e r a c t i o n s w i t h o t h e r w e a k acids: T h e e x a m p l e of the n e w u r i c o s u r i c d i u r e t i c tienilic a c i d (ticrynafen) w h i c h r e c e n t l y has b e e n w i t h d r a w n f r o m the m a r k e t b e c a u s e o f u n e x p e c t e d h e p a t o t o x i c i t y , s h o w s t h a t a d r u g o f this t y p e c o u l d c a u s e i m p o r t a n t i n t e r a c t i o n s at e x c r e t o r y m e c h a n i s m s ( K o s m a n , 1979; M c L a i n et al., 1980), b u t t h e s e h a d n e v e r b e e n s t u d i e d in a p r o s p e c t i v e m a n n e r b e f o r e release of t h e drug. P o s s i b l e d r u g i n t e r a c t i o n s with u r i c o s u r i c d r u g b e n z i o d a r o n e , w h i c h is w i d e l y used in c e n t r a l E u r o p e , h a v e n o t b e e n s t u d i e d at all. A n y d r u g w h i c h interferes w i t h the t r a n s p o r t of w e a k l y a c i d e n d o g e n o u s c o m p o u n d s s u c h as uric a c i d m a y p o t e n t i a l l y i n t e r a c t w i t h any other acid drug or drug metabolite. REFERENCES AMERICANPHARMACEUTICALASSOCIATION(1978) Evaluations of drug interactions. 2nd Ed., 2nd printing. Amer. Pharm. Ass., Washington, D.C. ANDREASEN,F., SIGURD, B. and STEINESS,E. (1980) Effect of probenecid on excretion and natriuretic action of furosemide. Fur. J. clin. Pharmac. 18: 489-495. BARTOLI, E., ARRAS,S., FAEDDA,R., lOGGIA, G., SATTA,A. and OLMEO, N. A. (1980) Blunting of furosemide diuresis by aspirin in man. J. clin. Pharmac. 20: 452-458. BECKETT, A. H. and ROWLAND, M. (1965) Urinary excretion kinetics of amphetamine in man. J. Pharm. Pharmac. 17: 628-639. BENET, L. Z. (1979) Pharmacokinetics/pharmacodynamics of furosemide in man: A review. J. Pharmacokin. Biopharm. 7: 1-27. BENNETT,W. M., PORTER,G. A., BAGBY,S. P. and McDONALD, W. J. (1979) Drugs and renal disease. ChurchillLivingstone, New York. BRATER, D. C. (1978) Effects of probenecid on furosemide response. Clin. Pharmac. Ther. 24: 548-554. BROOKS, P. M., BELL, M. A., STURROCK,R. D., FAMAEY,J. P. and DICK, W. C. (1974) The clinical significance of indomethacin-probenecid interaction. Br. J. clin, Pharmac. l: 287-290. BROWN, D. D., DORMOIS,J. C., ABRAHAM,G. N., LEWIS,R. N. and DIXON, K. (1976) Effect of furosemide on the renal excretion of digoxin. Clin. Pharmac. Ther. 20: 395-400. BURKLE, W. S. and MATZKE, G. R. (1979) Effect of quinidine on serum digoxin concentrations. Am. J. hosp. Pharm. 36: 968-971. CHAMBERS,G., KERRY, R. J. and OWEN, G. (1977) Lithium used with a diuretic. Br. reed. J. 2: 805-806. CUTLER, R. E., FORREY,A. W., CHRISTOPHER,T. G. and KIMPEL,B. M. (1974) Pharmacokinetics of furosemide in normal subjects and functionally anephric patients. Clin. Pharmac. Ther. 15: 588-596. DAHLQV1ST,R., EJVINSSON,G. and SCHENCK-GUSTAFSSON,K. (1980) Effect of quinidine on plasma concentration and renal clearance of digoxin A clinically important drug interaction. Br. J. clin. Pharmac. 9: 413-418. DESPOPOULOS,A. (1965) A definition of substrate specificity in renal transport of organic anions. J. theor. Biol. 8: 163-192. DODDS, M. G. and FOORD, R, D. (1970) Enhancement by potent diuretics of renal tubular necrosis induced by cephaloridine. Br. J. Pharmac. 40: 227-230. DOERING, W. (1979) Quinidine-digoxin interaction: Pharmacokinetics, underlying mechanisms and clinical implications. N e w Engl. J. Med. 301 : 40(0404. EJVINSSON,G. (1978) Effect of quinidine on plasma concentrations of digoxin. Br. reed. J. l: 279-280. FENSTER, P. E., POWELL,J. R,, GRAVES,P. E., CONRAD, K. A., HAGER,W. D., GOLDMAN, S. and MARCUS, F. 1. (1980) Digitoxin-quinidine interaction: Pharmacokinetic evaluation. Ann. int. Med. 93: 698-701. FIELD, J. B., OHTA, M., BOYLE,C. and REMER, A. (1967) Potentiation of the hypoglycemic effect of acetohexamide by phenylbutazone, N e w Engl. J. Med. 277: 889-890. FROLICH,J. C., HOLLIF1ELD,J. W., DORMOIS,J. C., FROLICH,B. L., SEYBERTH,H., MICHELAKIS,A. M. and OATES, J. A. (1976) Suppression of plasma renin activity by indomethacin in man. Circ. Res. 39: 447-452. GERHARDT, R. E., KNOUSS,R. F., THYRUM,P. T., LUCHI, R. J. and MORRIS, J. J. (1969) Quinidine excretion in aciduria and alkaluria. Ann. int. Med. 71:927 933. GLEN, A. I. M. (1976) Lithium Its indications, use and clinical implications. In: Topics in therapeutics 2, pp. 19(~203, TURNER, P. (ed) Pitman, London. GOLD, H., MODELL, W. and PRICE, L. (1932) Combined actions of quinidine and digitalis on the heart: An experimental study. Arch. int. Med. 50: 766-769. GRIFFIN, J. P., D'ARcY, P. F. (1979) A Manual of Adcerse Drug Interactions. 2nd Edition, Wright, Bristol. HAGER, W. D., FENSTER,P., MAYERSOHN,M., PERRIER,O., GRAVES,P., MARCUS,F. I. and GOLDMAN,S. (1979) Digoxin quinidine interaction. N e w Engl. J. Med. 300: 1238-1241. HANSTEN, P. D. (1976) Drug interactions. Lea & Febiger, Philadelphia. HONARI,J., BLAIR,A. D. and CUTLER, R. E. (1977) Effects of probenecid on furosemide kinetics and natriuresis in man. Clin. Pharmac. Ther. 22: 395-401. HOLT, D. W., HAYLER,A. M., EDMONDS,M. E., ASHEORD,R. F. (1979) Clinically significant interaction between digoxin and quinidine. Br. reed. J. 2: 1401. HOME1DA,M.. ROBERTS,C. and BRANCH,R. A. (1977) Influence ofprobenecid and spironolactone on furosemide kinetics and dynamics in man. Clin. Pharmac. Ther. 22: 402-409. HOOYMANS,P. M. and MERKUS,F. W. H. M. (1978) Effect of quinidine on plasma concentration of digoxin. Br. reed. J. 2: 1022.
78
L. OFFERHAUS
JEEEERSON, J. W. (1980) Diuretics are dangerous with lithium. Br. med. J. 2: 1217. KAMPMANN, J., MOLHOLM HANSEN, J., SIERSBAEK-NIELSEN, K. and LAURSEN, H. (1972) Effect of some drugs on penicillin half-life in blood. Clin. Pharmae. Ther. 13: 516- 519. KELLY, M. R., CUTt.ER, R. E., FORREY, A. W. and KIMPEL, B. M. (1974) Pharmacokinetics of orally administered furosemide. Clin. Pharmac. Ther. 1 5 : 1 7 8 186. KOcH-WESER, J. and GREENBLAT1, D. J. (1977) Drug interactions in clinical perspective. Eur. J. olin. Pharmu{'. I 1 : 405~408. KOSMAN, M. E. (1979) Evaluation of a new uricosuric diuretic Ticrynafen. J. Am. rned. Ass. 242:2876 2878. LEAHEY, E. B., REIFFEL, J. A., DRUSIN, R. E., HEISSENBUTTEL. R. H., LOVEJOY, W. P. and BIG¢;ER, J. T. (I978) Interaction between quinidine and digoxin. J. Am. reed. Ass. 240:533 534. LEAHEY, E. B., REIFFEL. J. A., HEISSENBUTTEL, R. H., DRUSIN, R. E., LovtJoY, W. P. and BIGGER, J, T. {1979} Arch. int. Med. 139:519 521. LEAHEV, E. B., REIFFEL, J. A., GIARDINA, E.-G. V. and BIGGER, J. T. (1980) The effect of quinidine and other oral antiarrhythmic drugs on serum digoxin A prospective study. Ann. mr. Med. 92:605 608. LICHE'~, J., SCHRODER, R. and RtETBROCK, N. (1977} The effect of oral spironolactone and intravenous canrenoate-K on the digoxin radioimmunoassay. Int. J. olin. Pharmac. 15:557 559. MAY, F. E., STEWART, R. B. and CI.UEE, L. E. (1977} Drug interactions and multiple drug administration. CID~. Pharmac. Ther. 22:322 328. MCLAIN, D. A., GARRI¢;A, F. J. and KANTOR, O. S. (1980) Adverse reactions associated with ticrynafen use. J. Am. med. Ass. 243:763 764. MUNGALL, D. R., ROBICHAUX, R. P., PERRY, W., SCOTT. J. W., ROBINSON, A., BURELLE, T. and HURST. D. (1980) Effects of quinidine on serum digoxin concentrations. Ann. int. Meal. 93:689 693. OCHS. H. R., PABST, J., GREENBLATT, D. J. and DENGI.ER, H. J. (1980) Non-interaction of digitoxin and quinidine. New Eng'l. J. Med. 303: 672- 674. ODLIND, B. and BEERMANN, B. {1980} Renal tubular secretion and effects of furosemide. Clin. Pharmac. Ther. 27: 784 790. OEFERHAL'S, L. (1973} Pharmacological backgrounds of drug interaction. Neth. J. Med. 16:230 236. PETERS, L. (1960) Renal tubular excretion of organic bases. Pharmae. Rez'. 12:1 35. PETERS, U., RISLER, T., GRABENSEE, B., EALKENSTE[N, U. and KROUKOU, J. (1980) lnteraktion yon Chinidin und Digitoxin beim Menschen. Dtseh. reed. Wsehr. 105:438 442. PETERSEN. V., HVIDT, S., THOMSEN, K. and SCHOU, M. {1974) Effect of prolonged thiazide treatment on renal lithium clearance. Br. reed. J. 3:143 145. RAMSAY, L. E., HARRISON, I. R., SftELTON, J. R. and VOSE, C. W. (1976) Influence of acetylsalicylic acid on the renal handling of a spironolactone metabolite in healthy subjects. Eur. J. olin. Pharmac. 10: 43M.8. RAWLINS, M. D. and R{It TLEDGE, P. (to be published) Drug interactions due to changes in drug distribution. Pharmac. Ther. REID, P. R. and MEEK, A. G. (1979} Digoxin quinidine interaction. Johns Hopkins Med. J. 145:227 229. REIDENBERG, M. M. (1971} Renal Function and Drug, Action. Saunders. Philadelphia. RISLER, T., PETERS, U., GRABENSEE, B. and SEIPEL. L. (1979) Untersuchungen zur Interaktion von Chinidin und Digoxin beim Menschen. Dtseh. med. Wschr. 104: 1523-1526. RISLER, T., PETERS, U., GRABENSEE, B. and SEIPEL, L. {1980) Quinidine digoxin interaction. New En,g'l. J. Med. 302: 175. ROSENBAUM, A. H., MARUTA, T.. RICHEr.SON, E (1979) Clinical pharmacology Series on pharmacology in practice. 1. Drugs that alter the mood. II. Lithium. Mayo Clin. Proc. 54:401 407. SCHENCK-GUSTAFSSON, K. and DAHLQVlST. R. 11981} Pharmacokinetics of digoxin in patients subjected to the quinidine-digoxin interaction. Br. J. clin. Phurmac. 11:181 186. SMITH, D. E., GEE, W. L., BRATER, D. C., LIN. E. T. and BENET, L. Z. (1980} Preliminary evaluation of furosemide probenecid interaction in humans. J. phurm. S{'i. 69:571 575. STEINESS, E. (1974) Renal tubular secretion of digoxin. Circulation 50:103 107. THOMSEN, K. and SCHOU, M. (1968) Renal lithium excretion in man. Am. J. Physiol. 215:823 827. TWEEDDALE, M. G. and O{nLVIE, R. I. (1973) Antagonism of spironolactone-induced natriuresis in man. Ne~ Eng'l. J. Med. 289:198 200. WALDORFF, S., ANDERSEN, J. D,, HEEBOLL-NIELSt-_N.N., NIELSEN, O. G., MOLTKE, E., SORENSEN, U. and STEINESS, E. {t978) Spjronolactone-induced changes in digoxin kinetics. Clin. Pharmac. Ther. 24, 162 167. WANDELL, M., POWELL, J. R., HAGER, W. D., FENSTER, P. E., GRAVES, P. E., C{)NRAD, K. A, and GOLDMAN. S. (1980} Effect of quinine on digoxin kinetics. Clin. Pharmac. Ther. 28:425 430. WEINER, I. M. and MUDGE, G. H. (1964) Renal tubular mechanisms for excretion of organic acids and bases. Am. J. Med. 36:743 762. WIRTH, K. E., FROLICH. J. C.. HOLLIrEELD, J. W.. FAIKNER, F. C., SWEETMAN, B. S. and OATES, J. A. (1976) Metabolism of digitoxin in m a n and its modification by spironolactone. Eur. J. olin, Pharrnac. 9:345 354.
0163o7258 81 01(}069-10505.00 0 Copyright © 1981 Pergamon Press Lid
Specialist Subject Editors: P. F. D'ARcv and J. P. GRIFFIN
DRUG
INTERACTIONS
AT EXCRETORY
MECHANISMS
L. OFFERHAUS Netherlands Committee on the Evaluation o]" Medicines, P.O. Box 5811, 2280 H V Rijswijk (ZH), The Netherlands
1. INTRODUCTION Drugs and drug metabolites are excreted through active and passive mechanisms by the kidney and the biliary tract, and to a minor and variable extent by the lungs, through the skin, and in saliva, milk and sweat. Whereas the hepatobiliary route of excretion is only important for a limited number of drugs (e.g. ampicillin, digitoxin, glutethimide, phenprocoumon), which in addition may undergo extensive enterohepatic recirculation after reabsorption through the intestinal wall, most drugs and drug metabolites are excreted mainly by the kidney. Excretion, at least at plasma concentrations within the therapeutic range, will occur at a rate proportional to the amount of drug present in the body, either by passive glomerular filtration of the fraction of the drug not bound to plasma proteins, or by active tubular secretion, using two still poorly defined carrier mechanisms, one for weak acids (Despopoulos, 1965), and another for weak bases (Peters, 1960). Weak acids are excreted more rapidly in alkaline urine, weak bases more rapidly in acid urine. The main site of the tubular secretion of drugs is the proximal convoluted tubule. Nonionized, and therefore more lipid-soluble, drug will be passively and rapidly reabsorbed, whereas the ionized drug fraction will be excreted. As the relative proportion of ionized and nonionized drug, depending on the p K a of the drug, is determined by the pH of the tubular urine, any change of the pH will profoundly influence the reabsorption process. Moreover, the amount of drug reabsorbed by the tubular epithelium increases as the iso-osmotic reabsorption of water increases during the passage of urine down the nephron, and the relative concentration of the drug in the tubular urine rises. Drug interactions in the kidney are mainly influenced by competition (both during active secretion of the drug and during passive reabsorption) for the pump mechanism in the tubular cells, acids competing with acids and bases with bases (Weiner and Mudge, 1964); by changes in the luminal pH, and by changes in the urinary flow rate which will influence both the process of reabsorption and the pH (Bennett et al., 1979). Drug interactions can therefore be expected if drugs which are mainly secreted by the proximal convoluted tubule (Table 1) are used simultaneously. Moreover, drugs which depress glomerular filtration rate (e.g. many anti-inflammatory and antihypertensive drugs, triamterene) or impair the tubular reabsorption of drug molecules which are predominantly excreted by glomerular filtration, and partially reabsorbed in the tubules (e.g. lithium-, bromide- and fluoride-ions, digoxin) may change the renal clearance of such drugs. No obvious examples of drug interaction during biliary excretion due to competition of drugs for hepatobiliary excretion mechanisms are known. However, the excretion of drugs which undergo recirculation after intestinal reabsorption may be enhanced by the simultaneous administration of anion exchange resins, e.g. cholestyramine and colestipol. Despite the many hundreds of possible drug interactions during the excretory phase described in the pharmacological and pharmaceutical literature, many of them anecdotal and poorly documented, only very few of them are clinically important. The problem of drug interactions (particularly those occurring during excretion) has been "vastly overes69
70
L. OFFERHAUS TABLE 1. Drugs Excreted by the Proximal Convoluted "luhule Weak Acids Diuretics Acetazolamide Ethacrynic acid Frusemide Thiazide diuretics Spironolactone Uricosuric drugs Benziodarone Probenecid Sulfinpyrazone Anti-inflammatory drugs Acetylsalicylic acid Indomethacin Oxyphenbutazone Phenylbutazone Salicylic acid Others p-Aminosalicylic acid (PAS) Chlorpropamide Clofibrate (metabolite) Fusidic acid Methotrexate Nalidixic acid Penicillins Phenobarbital Sulfonamides Sulfonic acids (Dapsone)
Weak Bases Tricyclic antidepressants Amitryptiline Desmethylimipramine Imipramine Nortryptiline Others Amphetamines Chloroquine Dopamine Fenfluramine Histamine Morphine Pethidine Procaine Quinine Quinidine Thiamine
Adapted from: Reidenberg (1971), Wade and Beeley (1976), Bennett et al. (1979) and Griffin and D'Arcy (1979).
timated and its applicability exaggerated beyond all reason" (Koch-Weser and Greenblatt, 1977), and particularly interactions between anti-inflammatory drugs and diuretics have, in a sample of 10,518 hospitalized patients, not been shown to cause any clinical problems (May et al., 1977). Any discussion of drug interactions during the excretory phase should therefore be confined to those interactions which have been conclusively demonstrated in man and which are clinically relevant, i.e. those which influence the effectiveness or safety of drug therapy. Even so, drug interactions within this category are rarely dangerous. From the clinician's point of view the most important drugs known to cause this type of interaction belong to the following categories: (a) the loop-diuretics frusemide (furosemide) and ethacrynic acid; (b) the uricosuric drug probenecid; and (c) quinidine, which recently has been shown to reduce the renal excretion of digoxin. Other weakly acid drugs will only occasionally cause such interactions. 2. I N T E R A C T I O N S WITH A C I D D R U G S 2.1. FRUSEMIDE AND DRUG INTERACTIONS DURING THE EXCRETORY PHASE
Frusemide is a weakly acid derivative of anthranilic acid. 90~o of the absorbed fraction is eliminated by the kidney in unchanged form (mainly by proximal tubular secretion), and the remaining 10~o in the bile (Cutler et al., 1974; Kelly et al., 1974). On theoretical grounds one could expect probenecid to impair the diuretic effect of frusemide, because frusemide has to be secreted into the lumen of the proximal tubule in order to exert its diuretic effect (Odlind and Beermann, 1980), and probenecid could prevent frusemide access to the tubular lumen by blocking its cellular transport (Benet, 1979). The results obtained in studies in which the two drugs were given simultaneously (Honari et al., t977; Homeida et al., 1977; Brater, 1978; Andreasen et al., 1980) have, however, been extremely complex. Though pretreatment with probenecid decreases both the renal and the extrarenal clearance of frusemide, and increases its half-life by 540/o it does not alter
Drug interactions at excretory mechanisms
71
the ratio between urinary frusemide and urinary sodium. The amount of unchanged drug reaching the tubular lumen remains unchanged, and so does the total diuretic response. Because probenecid displaces frusemide from protein binding sites, the relatively higher fraction of unbound frusemide reaching the inside of the tubular lumen probably compensates for the reduction of the frusemide elimination (Smith et al., 1980). Both indomethacin (FriSlich et al., 1976; Benet, 1979) and acetylsalicylic acid (Bartoli et al., 1980) attenuate frusemide diuresis. Indomethacin pretreatinent reduces frusemide excretion by 18~o, urinary output by 23°.0 and sodium excretion by 28~o. Though the effect was attributed to prostaglandin-synthetase inhibition by indomethacin, Benet (1979) showed that indomethacin indeed inhibits frusemide elimination, but that the increased plasma levels of frusemide caused the amount of drug excreted unchanged in the urine to decrease only slightly. He therefore concluded that, though a pharmacokinetic interaction could be demonstrated, this could not explain the pharmacodynamic adverse effect of indomethacin on frusemide diuresis. In contrast to Benet's findings Bartoli et al. (1980) observed that a high i.v. dose (1.5 g) of acetylsalicylic acid reduced frusemide-induced sodium excretion by 29?o and urinary flow rate by 25°/o, and that those changes closely correlated with a decrease of the urinary clearance of frusemide. Moreover, acetylsalicylic acid alone did not change water and sodium output. These observations make a competition of frusemide and acetylsalicylic acid for the same carrier mechanism in the tubular cell likely. Frusemide may enhance the ototoxicity of aminoglycoside antibiotics (American Pharmaceutical Association, 1976), and the nephrotoxicity of cephaloridine (Dodds and Foord, 1970), particularly in patients with renal insufficiency. The mechanism of this interaction is poorly understood, but the increased toxicity is probably caused by the additive toxic properties of both drugs. Pharmacokinetic studies have not been done. Though frusemide-induced hypokalaemia may potentiate both the efficacy and the toxicity of cardiac glycosides, frusemide does not alter digoxin elimination or steady-state serum digoxin levels (Brown et al., 1976). Theoretically chronic treatment with frusemide might decrease lithium clearance, particularly in combination with dietary sodium restriction. However, though most reference texts on drug interactions mention this possibility, no cases of frusemide-induced lithium toxicity have been reported. Thiazide diuretics may raise serum lithium levels up to three times the normal value in lithium-induced nephrogenic diabetes insipidus (Rosenbaum et al., 1979), and the risk of combining these drugs is not inconsiderable (Jefferson, 1980), though the drugs may be combined if the serum lithium level is closely monitored (Chambers et al., 1977). However, the site of this interaction being the distal renal tubule, the same may not hold true for frusemide, which has its main site of action in the proximal tubule and Henle's loop (Thomsen and Schou, 1968). 2.2. ETHACRYNIC ACID AND DRUG INTERACTIONS DURING THE EXCRETORY PHASE In contrast to frusemide, interactions with ethacrynic acid have scarcely been studied. Hearing loss may occur if ethacrynic acid is combined with aminoglycoside antibiotics (i.e. kanamycin, gentamicin, neomycin, streptomycin and tobramycin), particularly in patients with renal insufficiency (American Pharmaceutical Association, 1978). The mechanism of this interaction is unknown. A pharmacokinetic interaction within the kidney has not been excluded, but concrete data are not available. 2.3. SPIRONOLACTONE AND DRUG INTERACTIONS DURING THE EXCRETORY PHASE 600 mg of acetylsalicylic acid given orally reduces the natriuretic effects of spironolactone in a single-dose experiment in normal subjects (Tweeddale and Ogilvie, 1973) by 13-24~o, depending on the dose of spironolactone, and by 30?o during chronic treatment with 25 mg spironolactone q.i.d. This observation has been confirmed by Ramsay et al. (1976). Acetylsalicylic acid probably blocks the carrier-mediated secretion of the principal
72
L. OFFERHAUS
spironolactone metabolite canrenone in the proximal convoluted tubule, thus blunting its diuretic effect. Spironolactone blocks the tubular secretion of digoxin (Steiness, 1974) but this, being only a minor elimination pathway of the drug, does not fully account for the raised serum levels of digoxin found during combined treatment with digoxin and spironolactone, because spironolactone reduces the volume of the deep digoxin compartment (Waldorff et al., 1978), and may compete for digoxin receptor sites. Digoxin dose should be reduced by approximately 30% in patients receiving spironolactone treatment. On the other hand, data on the well-known interaction between spironolactone and digitoxin seem to be conflicting because both a prolongation (Carruthers and Dujovne, 19801 and a reduction (Wirth et al., 1976) in digitoxin half-life during spironolactone treatment have been reported; no clinical data on enhanced digitoxin toxicity in spironolactone-treated patients are available. Many earlier studies have been confounded by the interference of the metabolite canrenone with the radioimmunoassay of cardiac glycosides using unspecific methods (Lichey et al., 1977). 2.4. PROBENEC1D AND DRUG INTERACTIONS DURING THE EXCRETORY PHASE Probenecid, a benzoic acid derivative, owes its uricosuric action to its ability to block the carrier-mediated transport of many weak organic acids from and into the tubular lumen. It promotes the excretion of uric acid by blocking its reabsorption through the tubular epithelium, and it blocks the tubular excretion of many acid drugs, e.g. penicillins, cephalosporins, dapsone, rifampicin, nitrofurantoin, sulphonamides, methotrexatc, salicylates (including p-aminosalicylic acid), some oral antidiabetics (chlorpropamide and acetohexamide), thiazide diuretics, and indomethacin. Most reports of these interactions are anecdotal and poorly documented, or clinically irrelevant. Prospective clinical pharmacological studies are almost non-existent, Very few of these interactions carry any risk in the clinical situation, either because the interacting drug has a wide margin of safety, or because indications to combine the drugs simply do not exist. Salicylates should certainly not be combined with probenecid, because they antagonise the uricosuric effect of probenecid (Hansten, 1976). On the other hand, probenecid is widely used to reduce the renal clearance of penicillins (particularly ampicillin, carbenicillin and methicillin) in order to obtain high plasma levels in severe infections, and in combination with cephalosporins (particularly cephalotin), though caution is necessary in patients with decreased renal function, because such high serum levels may cause ototoxicity. Furthermore, it might be used to enhance the clinical effect of indomethacin (Brooks et al., 1974) and to prolong the duration of action of this drug during the night. 2.5. OTHER WEAK ACIDS WHICH MIGHT CAUSE CLINICALLY IMPORTANT DRUG INTERACTIONS DURING THE EXCRETORY PHASE
Phenylbutazone and its principal metabolite oxyphenbutazone, as well as indomethacin, sulfinpyrazone and acetylsalicylic acid slow the renal excretion of penicillin (Kampmann et al., 1972, Brooks et al., 1974) and phenylbutazone potentiates the hypoglycaemic effect of acetohexamide (Field et al., 1967). Acetylsalicylic acid has been shown to compete with the tubular excretion of methotrexate (American Pharmaceutical Association, 1978), but definite clinical proof that acetylsalicylic acid increases the toxicity of methotrexate is lacking. Acetazolamide, being a carbonic anhydrase inhibitor, alkalises the urine, and so may counteract the urinary disinfectant properties of acidifying agents such as methenamine mandelate, -hippurate and mandelic acid, and it may reduce the renal clearance of quinidine by this mechanism (Gerhardt et al., 19691. 3. INTERACTIONS WITH BASIC DRUGS 3.1. QUINIDINE AND DRUG INTERACTIONS WITH CARDIAC GLYCOSIDES DURING THE EXCRETORY PHASE
An interaction between quinidine and digitalis has been suspected since the Dutch Austrian cardiologist, Wenckebach, 70 years ago stressed the extraordinary potency of
Drug interactions at excretory mechanisms
73
his antiarrhythmic combination pills containing a mixture of digitalis leaf powder, quinidine and strychnine. Already 50 years ago this combination was reported to be hazardous (Gold et al., 1932). The interaction has recently been rediscovered (Ejvinsson, 1978), and this report was followed by numerous other publications confirming that quinidine raises serum digoxin levels (Leahey et al., 1978; Hooymans and Merkus, 1978; Leahey et al., 1979; Burkle and Matzke, 1979; Reid and Meek, 1979; Holt et al., 1979; Leahey et al., 1980). Quinidine, on average, causes a twofold increase in serum digoxin concentration in approximately 90~o of all patients using this drug combination, though the interindividual variation seems to be considerable. The extent of the rise in serum digoxin is related to the quinidine dose. The mechanism of this interaction has been the subject of a number of studies, both in volunteers and in patients (Hager et al., 1979; Doering, 1979; Risler et al., 1979; Dahlqvist et al., 1980; Mungall et al., 1980; Schenck-Gustafsson and Dahlqvist, 1981). Two different mechanisms seem to be involved, because quinidine treatment causes both a decrease of the volume of distribution of digoxin by approximately 33~o and a decrease of the renal digoxin clearance varying from 33~o to 57~o without a statistically significant change in the glomerular filtration rate. Only in one study (Dahlqvist et al., 1980), a relatively high dose (1200mg daily) of a slow-release preparation of quinidine, given to patients with moderate impairment of renal function, effected a drop of 23~o in the glomerular filtration rate during quinidine treatment, but an even greater drop of 70~o in the renal digoxin clearance. It seems therefore that quinidine displaces digoxin from peripheral tissue binding sites (mainly located in striated muscle tissue) without affecting binding to cardiac receptors, and competes with digoxin for carrier-mediated excretion mechanisms in the proximal tubule. Both interaction mechanisms tend to elevate serum digoxin levels to an average of twice the normal steady-state levels, and often well within the toxic serum range. The mechanism for which the drugs compete in the kidney is saturable, because further increases in quinidine dosage lead to increased changes in the volume of distribution and increased serum levels of digoxin without further affecting renal digoxin clearance (Risler et al., 1980). The mechanism of the displacement interaction will be treated in another review article in this series (Rawlins and Routledge, 1982). The interaction between quinidine and digoxin is not just another pharmacokinetic curiosity, but it can be particularly hazardous and may manifest itself as cardiac arrhythmias and other typical symptoms of digitalis toxicity (Holt et al., 1979; Leahey et al., 1978, 1979). The quinidine isomer, quinine, seems to have a different effect on digoxin disposition (Wandell et al., 1980), because it increases half-life and serum digoxin levels, does not affect renal digoxin clearance, but does decrease non-renal (biliary) clearance of digoxin by an average of 55%. Though it has been claimed (Ochs et al., 1980) that quinidine does not change digitoxin kinetics in healthy volunteers, the results obtained by other groups have yielded conflicting results; Peters et al. (1980) reported a moderate (+32°/o) increase in serum digitoxin level and a similarly increased half-life, but no changes either in renal or extrarenal clearance of digitoxin; however, Fenster et al. (1980) found similar moderate changes, but in addition a small, but statistically significant, decrease in renal digitoxin clearance by 30% without changes in protein binding or volume of distribution of the drug. The mechanism of the quinidine-digitoxin interaction may therefore be different from that of the quinidine-digoxin interaction, and the clinical implications of these observations seem still obscure. Moreover, all three studies were done in healthy volunteers. Pharmacokinetic studies in patients have not yet been done, and cases of unexpected digitoxin toxicity in patients treated with the combination of quinidine and digitoxin have not yet been reported. 3.2. LITHIUM SALTS AND DRUG INTERACTIONS DURING THE EXCRETORY PHASE Lithium ions are filtered by the glomerulus, and approximately 8000 of the filtered amount is reabsorbed by the renal tubules. Lithium clearance is therefore approximately
Salicylates l ndomethacin Phenylbutazone Oxyphenbutazone Sulfinpyrazone Acetylsalicylic acid
Methotrexate Penicillins
Penicillins (ampicillin, Inhibition of tubular excretion of (2) carbenicillin, methicillin); cephalosporins, dapsone, rifampicin(?), nitrofurantoin, sulfonamides, methotrexate, salicylates, chlorpropamide, acetohexamide, indomethacin
Probenecid
Inhibition of tubular excretion of (2) Inhibition of tubular excretion of (2)
Inhibition of tubular excretion of (2)
Digoxin
Spironolactone
? Probably additive toxic action
Competition over tubular transport Displacement from protein binding sites Inhibition of tubular excretion of (1); depression of glomerular filtration rate by (2). Competition for tubular transport ? Probably additive toxic action ? Probably additive toxic action
Mechanism of Interaction
Aminoglycosides
Acetylsalicylic acid Aminoglycosides Cephaloridine
lndomethacin
Probenecid
Drug 2
Ethacrynic acid
Frusemide
Drug 1
Clinical Implications
Increased methotrexate toxicity Probably none
Increased serum concentrations of (2); increased toxicity; increased clinical effect in drugs with systemic activity; decreased efficacy in urinary tract infections,
Increased serum digoxin concentration
Increased risk of hearing loss
Decreased diuretic response Increased risk of hearing loss Increased risk of renal damage
Decreased diuretic response
None demonstrated
TABLE 2. Clinically Important Drug Interactions at Excretory Mechanisms
>
r-
Low Na+-intake: Increased toxicity High Na+-intake: Decreased efficacy Increased bone loss Decreased efficacy Decreased efficacy Increased toxicity Increased efficacy and/or toxicity of (2)
Competition over tubular reabsorption Same Increased urinary pH, increased lithium-clearance ? Increased tubular reabsorption of (2) Increased urinary pH
Sodium-ions
Calcium-ions Sodium bicarbonate "~ Acetazolamide J Aminophylline Thiazide diuretics
Amphetamines Quinidine Tetracyclines
Lithium
Sodium bicarbonate Antacids (high dose, long-term) Acetazolamide Thiazide diuretics
Digoxin
Quinine
Digitoxin
None demonstrated
Increased serum digoxin concentration and increased toxicity risk.
Not studied.
Higher quinidine serum concentrations, increased efficacy and toxicity.
Increased urinary pH
Inhibition of extrarenal excretion of (2).
Digoxin
Quinidine
Decreased efficacy in urinary tract infections.
Increased urinary pH
Displacement from tissue binding sites; inhibition of tubular excretion of (2) ? Inhibition of extrarenal excretion
Methenamine mandelate Mandelic acid Methenamine hippurate Quinidine
Acetazolamide
o
e.,.q-
76
L. OFFERHAUS
20°,o of that of creatinine, i.e. 15 30ml/min. Though Li + is only a small molecule (m.w. = 7) it is to a certain extent exchangeable with much larger cations such as Na t (m.w. = 23), Ca 2+ (m.w. = 40), and Mg 2+ (m.w. = 24). Sodium loading enhances lithium excretion, sodium deprivation promotes retention of lithium; it promotes renal Ca z +-loss and increases extracellular Mg 2+, and in vitro it has a K+-like action on (Na + + K+) ATPase. The clinical implications of the exchangeability of the Li+-ion may be lithiumintoxication on a low-sodium diet, and loss of bone density during long-term treatment (Glen, 1976). Renal lithium clearance will be enhanced by alkalinization of the urine (by sodium bicarbonate or acetazolamide), during urea-induced osmotic diuresis, and by concomitant administration of aminophylline (Thomsen and Schou, 1968). Though single doses of diuretics do not affect renal lithium clearance, long-term thiazide therapy reduces clearance by approximately 24~, independent of sodium intake (Petersen et al., 1974). Because indications for prescribing lithium and diuretics together may exist [e.g. lithium-induced nephrogenic diabetes insipidus (Rosenbaum et al., 1979), or the combination of endogenous depression and heart failure], lithium concentration should be particularly carefully monitored if these drugs are combined, and lithium dose should preferably be reduced by approximately 50~o. 4. DRUG INTERACTIONS DURING THE EXCRETORY PHASE CAUSED BY DRUG-INDUCED CHANGES IN URINARY pH The renal clearance of weak bases is pH-dependent, being low if the urine is alkaline, and high in the presence of acid urine. Drugs which increase urinary pH (e.g. sodium bicarbonate, long-term high-dose antacid therapy, acetazolamide, thiazide diuretics) may cause reduction of renal clearance and accumulation of certain weak bases such as quinidine, amphetamines and tetracyclines. This interaction has been used by professional cyclists who combined the use of amphetamines with high doses of sodium bicarbonate to enhance the stimulating effect and to reduce the chances of being caught out during urine doping checks (Offerhaus, 1973). Though this interaction has been thoroughly investigated (Beckett and Rowland, 1965), the declining use of these drugs in clinical medicine makes the interaction relatively unimportant. Theoretically quinidine disposition might be profoundly altered by changes in urinary pH (Gerhardt et al., 1969), but clinical problems due to interaction with acidifying or alkalizing drugs seem to be rare, because therapeutic doses of such drugs rarely change urinary pH outside its normal rather narrow limit of 4.6-8.0. 5. CONCLUSIONS Though some of the earliest reports on clinically relevant drug interactions concerned interactions due to tubular excretion mechanisms (e.g. probenecid-penicillin and quinidine-digoxin), and numerous others, most of them pharmacological curiosities, have since been discovered and described, the implications for the patient of this type of drug interaction are relatively few. With the sole exception of the quinidine-digoxin and the thiazide-lithium interaction they rarely cause important changes in drug elimination and disposition and they are only exceptionally the cause of iatrogenic illness. A synopsis of the clinically important drug interactions of this type is given in Table 2. The principal mechanism involved seems to be competition of weak bases on the one side and of weak acids on the other hand for their respective carrier-mediated active tubular transport mechanisms, i.e. excretion from serum into the tubular urine and reabsorption of filtered drug from tubular urine back into the blood stream. Because the involvement of tubular transport mechanisms in drug interactions can only be elucidated using sophisticated and complicated clinical pharmacological methods of investigation, it may well be possible that other examples of the same kind of interaction will be discovered in the future. Moreover, surprisingly little research has been done on the possible role of acid drug
Drug interactions at excretory mechanisms
77
m e t a b o l i t e s , w h i c h are k n o w n to c a u s e p r o t e i n b i n d i n g d i s p l a c e m e n t i n t e r a c t i o n s . M a n y w e a k l y a c i d d r u g s w h i c h are a l m o s t o r e n t i r e l y e x c r e t e d in u n c h a n g e d f o r m by t h e k i d n e y m a y p o t e n t i a l l y c a u s e s u c h i n t e r a c t i o n s w i t h o t h e r w e a k acids: T h e e x a m p l e of the n e w u r i c o s u r i c d i u r e t i c tienilic a c i d (ticrynafen) w h i c h r e c e n t l y has b e e n w i t h d r a w n f r o m the m a r k e t b e c a u s e o f u n e x p e c t e d h e p a t o t o x i c i t y , s h o w s t h a t a d r u g o f this t y p e c o u l d c a u s e i m p o r t a n t i n t e r a c t i o n s at e x c r e t o r y m e c h a n i s m s ( K o s m a n , 1979; M c L a i n et al., 1980), b u t t h e s e h a d n e v e r b e e n s t u d i e d in a p r o s p e c t i v e m a n n e r b e f o r e release of t h e drug. P o s s i b l e d r u g i n t e r a c t i o n s with u r i c o s u r i c d r u g b e n z i o d a r o n e , w h i c h is w i d e l y used in c e n t r a l E u r o p e , h a v e n o t b e e n s t u d i e d at all. A n y d r u g w h i c h interferes w i t h the t r a n s p o r t of w e a k l y a c i d e n d o g e n o u s c o m p o u n d s s u c h as uric a c i d m a y p o t e n t i a l l y i n t e r a c t w i t h any other acid drug or drug metabolite. REFERENCES AMERICANPHARMACEUTICALASSOCIATION(1978) Evaluations of drug interactions. 2nd Ed., 2nd printing. Amer. Pharm. Ass., Washington, D.C. ANDREASEN,F., SIGURD, B. and STEINESS,E. (1980) Effect of probenecid on excretion and natriuretic action of furosemide. Fur. J. clin. Pharmac. 18: 489-495. BARTOLI, E., ARRAS,S., FAEDDA,R., lOGGIA, G., SATTA,A. and OLMEO, N. A. (1980) Blunting of furosemide diuresis by aspirin in man. J. clin. Pharmac. 20: 452-458. BECKETT, A. H. and ROWLAND, M. 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