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Kidney Disease and Drug Metabolism
Indiddualization of Drug Therapy Symposium on Individualization
Kidney Disease and Drug Metabolism Marcus M. Reidenberg, M.D.* M.D."'
Drug excretion is slowed in patients with poor renal function. Methods for modifying ordinary drug dosage for uremic patients to allow for this decreased excretion have been presented by Dettli in this volume others.3,3 , 22 22 and by others. Most drugs are metabolized to inactive compounds prior to excretion rather than being excreted unchanged. For such drugs, the metabolism pathway is the "route of elimination" of the drug, since this biotransformation.of mation .of the drug molecule removes the pharmacologic activity from the body. The subsequent excretion of the inert metabolites is of much less pharmacologic importance. The chemical reactions of drug metabolism have been classified into four broad groups: oxidations, reductions, hydrolyses, and syntheses. One can study the elimination rate or plasma half-life of a variety of metabolized drugs in normal and uremic subjects. If one then groups these drugs by their major pathway of metabolism (Table 1), generalizations appear. Drug oxidations, the major pathways of drug metabolism, appear normal in uremia. The reduction pathway appears slow. Glucuronide conjugation is normal. Isoniazid acetylation is normal, whereas sulfisoxazole and PAS acetylation appear slow. This may mean that the polymorphic (INH) acetylating system is not slowed by uremia but that the monomorphic acetylating system is. The elimination of many peptides is normal in uremic patients, yet the metabolism of insulin is slowed. Plasma cholinesterase activity is decreased in uremia. The mechanism for decreased drug metabolism in uremia has been studied, using the pathway of hydrolysis of the local anesthetic drug 23 procaine (Novocaine) by plasma pseudocholinesterase as the example. 23 This drug metabolism pathway is slowed in uremia, with the degree of slowing being proportional to the degree of elevation of the patient's BUN (Fig. 1). Dialysis of patients, or in vitro dialysis of plasma from uremic patients, failed to increase the hydrolysis rate of procaine. Adding urea to normal serum to final concentration of as high as 1600 mg/IOO mg/ 1 00 ml did not slow the normal rate of procaine metabolism. Enzyme kinetic measurements made in one patient showed a normal Michaelis constant ':'Associate *Associate Professor, Pharmacology and Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania
Vo!. 58, No. 5, September 1974 Medical Clinics of North America- Vol.
1059
1060
MARCUS M. REIDENBERG
Table 1.
Effect of Uremia on Apparent Elimination Rate of Drugs in Man
DRUG
EFFECT
Tolbutamide Tolbutamide Phenobarbital Histamine Phenacetin Diphenylhydantoin Antipyrine Quinidine Propranolol Vitamin D Vitanlin
Oxidations None None None None None None None None None Prolonged
Cortisol
Reduction Prolonged
Chloramphenicol Salicylic acid Sulfisoxazole p-Aminosalicylate Isoniazid Isoniazid
Plasma angiotensinase
L-Asparaginase LAsparaginase
Plasma kallikreinogen Insulin Cholinesterase activity Procaine
Syntheses Glucuronide Conjugation None Glycine Conjugation None Acetylation Prolonged Prolonged None None Hydrolyses Peptides None None None Prolonged Esters I Slowed Prolonged )
REFERENCE
Glogner~ Glogner" 21 Reidenberg 21 Fabre Fabre'8 Beall 2 BealF 2O Prescott2() Prescott l' Letteri l4 Black Black'4 Kessler l212 lO Lowenthal 15 AviolPl Avioli
Englert 7 Englert7
l3 Kunin 1a 16 Lowenthal 16 24 Reidenberg 24 Oggl8 Ogg18 Bowersox Bowersox"5 Reidenberg 5
Osbornl~ Osborn l" HOlD Holo Colman 66 O'Brien l7 ll Holmes l1 Reidenberg 223:3
(km) for the patient but a low maximum metabolizing capacity (V max). All these observations indicate that the reason for the slowed procaine hydrolysis in serum from uremic patients is that there is a low level of enun excreted competitive inhibitor of zyme present and not that there is an unexcreted the enzyme in the uremic serum. To prove this, uremic serum was mixed with normal serum. The resultant enzyme activity measured was no lower than one would expect if the low level uremic serum simply diluted the enzyme in the normal serum. There was nothing in the study to indicate that the uremic serum contained an inhibitor of plasma pseudocholinesterase. Thus one can conclude that for this pathway of drug metabolism, the reason for its impairment in uremia is that low levels of drug metabolizing enzyme are present and not that there is an unexcreted inhibitor present in the uremic serum.
1061
KIDNEY DISEASE AND DRUG METABOLISM
32 3.2
•
PROCAINE HALF-LIFE vs
BUN BUN
28 2.8
2.4
T/2 1/2 (min)
2.0 2.0
1.6 1.6
12 1.2 0.8 0.4 0 O-fllll-......-
o0
20
40
...- . ..-III-. .60
80
lOO 100
BUN BUN
120
....- , . . .. . .-~
140
160
180
200
Figure 1. Half-life of procaine in sera from patients with impaired renal function plotted against the patient's blood urea nitrogen concentration. The mean ± 1 std. dev. of 12 healthy volunteers is shown for comparison. Regression analysis for the patient group showed procaine half-life = 0.011 BUN + 0.125, r == 0.55, p<0.05.
Uremic patients have slowing of certain pathways of drug metabolism as well as drug excretion. Although the major pathways of drug metabolism, oxidation, and glucuronide conjugation appear normal in uremia, some of the minor pathways of drug metabolism are slowed. Thus most metabolized drugs will not accumulate if given to uremic patients at ordinary doses. Some drugs such as p-aminosalicylic acid, sulfisoxazole (Gantrisin) and some other sulfonamides, and hydralazine (Apresoline) are metabolized slowly in uremia. Procaine and the other ester type local anesthetics would also be in the slow metabolism class for uremic patients. If drugs in these groups are given at ordinary dosage to uremic patients, excessive accumulation of the drug may well occur.
REFERENCES 1. Avioli, L. V., Birge, S., Lee, S. W., and Slatopolsky, E.: The metabolic fate of vitamin D: D,-"H 3-:3H in chronic renal failure. J. Clin. Invest., 47:2239-2252, 1968. 2. Beall, G. N., and Van Arsdel, P. P.: Histamine metabolism in human disease. J. Clin. In39:676-683,1960. vest., 39 :676-683, 1960. 3. Bennett, W. M., Singer, I., and Coggins, C. H.: Guide to drug usage in adult patients with impaired renal function. J.A.M.A., 223:991-997,1973. 4. Black, M.: Personal communication, 1972. Orme, B., and Barron, E.: Isoniazid 5. Bowersox, D. W., Winterbauer, R. H., Stewart, G. L., Grme, dosage in patients with renal failure. New Engl. J. Med., 289:84-87,1973. Mas9n, J. W., and Sherry, S.: The kallikreinogen-kallikrein enzyme system 6. Colman, R. W., Maspn, :763-777, 1969. of human plasma. Ann. Intern. Med., 71 :763-777,1969. 7. Englert, E., Brown, H., Willardson, D. G., Wallach, S., and Simons, E. L.: Metabolism of free and conjugated 17-hydroxycorticosteroids in subjects with uremia. J. Clin. Endocr., 18:36-48,1958. 18 :36-48, 1958. 8. Fabre, J., Freudenreich, J. De, Duckert, A., Pitton, J. S., Rudhart, M., and Virieux, C.: Influence of renal insufficiency on the excretion of chloroquine, phenobarbital, phenothia33:307-316, 1967. zines, and methacycline. Helv. Med. Acta, 33:307-316,1967. 9. Glogner, P., Lange, H., and Pfab, R.: Tolbutamidstoffwechsel bei Niereninsuffizienz. Med. Welt, 52:2876-2878,1968.
1062
MARCUS M. REIDENBERG
10. Ho, D. H. W., Thetford, B., Carter, C. J. K., and Frei, E.: Clinical pharmacological studies of L-asparaginase. Clin. Pharmacol. Ther., 11 :408-417, 1970. 11. Holmes, J. H., Nakamoto, S., and Sawyer, K. C.: Changes in blood composition before and after dialysis with the Kolff twin coil kidney. Trans. Amer. Soc. Artif. Intern. Organs, 4:16-23,1958. 4: 16-23, 1958. 12. Kessler, K. M., Lowenthal, D. T., Gibson, T., Warner, H., and Reidenberg, M. M.: Unimpaired quinidine elimination in patients with poor renal function or congestive heart failure. New Engl. J Med., 290:706-709, 1974. 13. Kunin, C. M., Glazko, A. J., and Finland, M.: Persistence of antibiotics in the blood of patients with acute renal failure. 11. Chloramphenicol and its metabolic products in the blood of patients with severe renal disease or hepatic cirrhosis. J. Clin. Invest., 38: 14981508, 1959. 14. Letteri, J. M., Mellk, H., Louis, S., Kutt, H., Durante, P., and Glazko, A.: Diphenylhydantoin metabolism in uremia. New Engl. J. Med., 285:648-652, 1971. 15. Lowenthal, D. T., Briggs, W. A., Gibson, T. P., Matusik, E., and Demaree, G.: Propranolol T'/2 in chronic renal disease. Pharmacologist, 15: 15:188, Tl/2 188, 1973. 16. Lowenthal, D. T., Briggs, W. A., and Levy, G.: Kinetics of salicylate elimination by anephric patients. Clin. Pharmacol. Ther., 15:211, 1974. 131 ) disap17. O'Brien, J. P., and Sharp, A. R.: The influence of renal disease on the insulin (1 (J131) pearance curve in man. Metabolism, 16:76-83,1967. 16:76-83, 1967. 18. Ogg, C. S., Toseland, P. A., and Cameron, J. S.: Pulmonary tuberculosis in patient on 2:283-284,1968. hemodialysis. Brit. Med. J., 2:283-284, 1968. 19. Osborn, E. C., Jerums, G., and JuPP, B. A.: Blood angiotensinase activity in relation to the breakdown of angiotensin 11 II amide and nonisotopic phenylthiocarbamyl angiotensin II amide in hypertensive and normotensive patients. Cardiovasc. Res., 2:33-38,1968. 2 :33-38, 1968. 20. Prescott, L. F.: The metabolism of phenacetin in patients with renal disease. Clin. Pharmacol. Ther., 10:383-394, 1969. 21. Reidenberg, M. M.: Effect of kidney disease on pharmacokinetics and drug response. Proc. 3:174-181,1972. 5th Int. Congr. Pharmacology, 3:174-181, 1972. 22. Reidenberg, M. M.: Renal Function and Drug Action. Philadelphia, W. B. Saunders Co., 1971. 23. Reidenberg, M. M., James, M., and Dring, L. G.: The rate of procaine hydrolysis in serum of normal subjects and diseased patients. Clin. Pharmacol. Ther., 13:279-284, 13 :279-284, 1972. 24. Reidenberg, M. M., Kostenbauder, H., and Adams, W.: The rate of drug metabolism in obese volunteers before and during starvation and in azotemic patients. Metabolism, 18 :209-213, 1969. 25. Reidenberg, M. M., Shear, L., and Cohen, R. V.: Isoniazid elimination in patients with impaired renal function. Amer. Rev. Respir. Dis., 108:1426-1428, 1973. Departments of Pharmacology and Medicine Temple University School of Medicine Philadelphia, Pennsylvania 19140
Kidney Disease and Drug Metabolism Marcus M. Reidenberg, M.D.* M.D."'
Drug excretion is slowed in patients with poor renal function. Methods for modifying ordinary drug dosage for uremic patients to allow for this decreased excretion have been presented by Dettli in this volume others.3,3 , 22 22 and by others. Most drugs are metabolized to inactive compounds prior to excretion rather than being excreted unchanged. For such drugs, the metabolism pathway is the "route of elimination" of the drug, since this biotransformation.of mation .of the drug molecule removes the pharmacologic activity from the body. The subsequent excretion of the inert metabolites is of much less pharmacologic importance. The chemical reactions of drug metabolism have been classified into four broad groups: oxidations, reductions, hydrolyses, and syntheses. One can study the elimination rate or plasma half-life of a variety of metabolized drugs in normal and uremic subjects. If one then groups these drugs by their major pathway of metabolism (Table 1), generalizations appear. Drug oxidations, the major pathways of drug metabolism, appear normal in uremia. The reduction pathway appears slow. Glucuronide conjugation is normal. Isoniazid acetylation is normal, whereas sulfisoxazole and PAS acetylation appear slow. This may mean that the polymorphic (INH) acetylating system is not slowed by uremia but that the monomorphic acetylating system is. The elimination of many peptides is normal in uremic patients, yet the metabolism of insulin is slowed. Plasma cholinesterase activity is decreased in uremia. The mechanism for decreased drug metabolism in uremia has been studied, using the pathway of hydrolysis of the local anesthetic drug 23 procaine (Novocaine) by plasma pseudocholinesterase as the example. 23 This drug metabolism pathway is slowed in uremia, with the degree of slowing being proportional to the degree of elevation of the patient's BUN (Fig. 1). Dialysis of patients, or in vitro dialysis of plasma from uremic patients, failed to increase the hydrolysis rate of procaine. Adding urea to normal serum to final concentration of as high as 1600 mg/IOO mg/ 1 00 ml did not slow the normal rate of procaine metabolism. Enzyme kinetic measurements made in one patient showed a normal Michaelis constant ':'Associate *Associate Professor, Pharmacology and Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania
Vo!. 58, No. 5, September 1974 Medical Clinics of North America- Vol.
1059
1060
MARCUS M. REIDENBERG
Table 1.
Effect of Uremia on Apparent Elimination Rate of Drugs in Man
DRUG
EFFECT
Tolbutamide Tolbutamide Phenobarbital Histamine Phenacetin Diphenylhydantoin Antipyrine Quinidine Propranolol Vitamin D Vitanlin
Oxidations None None None None None None None None None Prolonged
Cortisol
Reduction Prolonged
Chloramphenicol Salicylic acid Sulfisoxazole p-Aminosalicylate Isoniazid Isoniazid
Plasma angiotensinase
L-Asparaginase LAsparaginase
Plasma kallikreinogen Insulin Cholinesterase activity Procaine
Syntheses Glucuronide Conjugation None Glycine Conjugation None Acetylation Prolonged Prolonged None None Hydrolyses Peptides None None None Prolonged Esters I Slowed Prolonged )
REFERENCE
Glogner~ Glogner" 21 Reidenberg 21 Fabre Fabre'8 Beall 2 BealF 2O Prescott2() Prescott l' Letteri l4 Black Black'4 Kessler l212 lO Lowenthal 15 AviolPl Avioli
Englert 7 Englert7
l3 Kunin 1a 16 Lowenthal 16 24 Reidenberg 24 Oggl8 Ogg18 Bowersox Bowersox"5 Reidenberg 5
Osbornl~ Osborn l" HOlD Holo Colman 66 O'Brien l7 ll Holmes l1 Reidenberg 223:3
(km) for the patient but a low maximum metabolizing capacity (V max). All these observations indicate that the reason for the slowed procaine hydrolysis in serum from uremic patients is that there is a low level of enun excreted competitive inhibitor of zyme present and not that there is an unexcreted the enzyme in the uremic serum. To prove this, uremic serum was mixed with normal serum. The resultant enzyme activity measured was no lower than one would expect if the low level uremic serum simply diluted the enzyme in the normal serum. There was nothing in the study to indicate that the uremic serum contained an inhibitor of plasma pseudocholinesterase. Thus one can conclude that for this pathway of drug metabolism, the reason for its impairment in uremia is that low levels of drug metabolizing enzyme are present and not that there is an unexcreted inhibitor present in the uremic serum.
1061
KIDNEY DISEASE AND DRUG METABOLISM
32 3.2
•
PROCAINE HALF-LIFE vs
BUN BUN
28 2.8
2.4
T/2 1/2 (min)
2.0 2.0
1.6 1.6
12 1.2 0.8 0.4 0 O-fllll-......-
o0
20
40
...- . ..-III-. .60
80
lOO 100
BUN BUN
120
....- , . . .. . .-~
140
160
180
200
Figure 1. Half-life of procaine in sera from patients with impaired renal function plotted against the patient's blood urea nitrogen concentration. The mean ± 1 std. dev. of 12 healthy volunteers is shown for comparison. Regression analysis for the patient group showed procaine half-life = 0.011 BUN + 0.125, r == 0.55, p<0.05.
Uremic patients have slowing of certain pathways of drug metabolism as well as drug excretion. Although the major pathways of drug metabolism, oxidation, and glucuronide conjugation appear normal in uremia, some of the minor pathways of drug metabolism are slowed. Thus most metabolized drugs will not accumulate if given to uremic patients at ordinary doses. Some drugs such as p-aminosalicylic acid, sulfisoxazole (Gantrisin) and some other sulfonamides, and hydralazine (Apresoline) are metabolized slowly in uremia. Procaine and the other ester type local anesthetics would also be in the slow metabolism class for uremic patients. If drugs in these groups are given at ordinary dosage to uremic patients, excessive accumulation of the drug may well occur.
REFERENCES 1. Avioli, L. V., Birge, S., Lee, S. W., and Slatopolsky, E.: The metabolic fate of vitamin D: D,-"H 3-:3H in chronic renal failure. J. Clin. Invest., 47:2239-2252, 1968. 2. Beall, G. N., and Van Arsdel, P. P.: Histamine metabolism in human disease. J. Clin. In39:676-683,1960. vest., 39 :676-683, 1960. 3. Bennett, W. M., Singer, I., and Coggins, C. H.: Guide to drug usage in adult patients with impaired renal function. J.A.M.A., 223:991-997,1973. 4. Black, M.: Personal communication, 1972. Orme, B., and Barron, E.: Isoniazid 5. Bowersox, D. W., Winterbauer, R. H., Stewart, G. L., Grme, dosage in patients with renal failure. New Engl. J. Med., 289:84-87,1973. Mas9n, J. W., and Sherry, S.: The kallikreinogen-kallikrein enzyme system 6. Colman, R. W., Maspn, :763-777, 1969. of human plasma. Ann. Intern. Med., 71 :763-777,1969. 7. Englert, E., Brown, H., Willardson, D. G., Wallach, S., and Simons, E. L.: Metabolism of free and conjugated 17-hydroxycorticosteroids in subjects with uremia. J. Clin. Endocr., 18:36-48,1958. 18 :36-48, 1958. 8. Fabre, J., Freudenreich, J. De, Duckert, A., Pitton, J. S., Rudhart, M., and Virieux, C.: Influence of renal insufficiency on the excretion of chloroquine, phenobarbital, phenothia33:307-316, 1967. zines, and methacycline. Helv. Med. Acta, 33:307-316,1967. 9. Glogner, P., Lange, H., and Pfab, R.: Tolbutamidstoffwechsel bei Niereninsuffizienz. Med. Welt, 52:2876-2878,1968.
1062
MARCUS M. REIDENBERG
10. Ho, D. H. W., Thetford, B., Carter, C. J. K., and Frei, E.: Clinical pharmacological studies of L-asparaginase. Clin. Pharmacol. Ther., 11 :408-417, 1970. 11. Holmes, J. H., Nakamoto, S., and Sawyer, K. C.: Changes in blood composition before and after dialysis with the Kolff twin coil kidney. Trans. Amer. Soc. Artif. Intern. Organs, 4:16-23,1958. 4: 16-23, 1958. 12. Kessler, K. M., Lowenthal, D. T., Gibson, T., Warner, H., and Reidenberg, M. M.: Unimpaired quinidine elimination in patients with poor renal function or congestive heart failure. New Engl. J Med., 290:706-709, 1974. 13. Kunin, C. M., Glazko, A. J., and Finland, M.: Persistence of antibiotics in the blood of patients with acute renal failure. 11. Chloramphenicol and its metabolic products in the blood of patients with severe renal disease or hepatic cirrhosis. J. Clin. Invest., 38: 14981508, 1959. 14. Letteri, J. M., Mellk, H., Louis, S., Kutt, H., Durante, P., and Glazko, A.: Diphenylhydantoin metabolism in uremia. New Engl. J. Med., 285:648-652, 1971. 15. Lowenthal, D. T., Briggs, W. A., Gibson, T. P., Matusik, E., and Demaree, G.: Propranolol T'/2 in chronic renal disease. Pharmacologist, 15: 15:188, Tl/2 188, 1973. 16. Lowenthal, D. T., Briggs, W. A., and Levy, G.: Kinetics of salicylate elimination by anephric patients. Clin. Pharmacol. Ther., 15:211, 1974. 131 ) disap17. O'Brien, J. P., and Sharp, A. R.: The influence of renal disease on the insulin (1 (J131) pearance curve in man. Metabolism, 16:76-83,1967. 16:76-83, 1967. 18. Ogg, C. S., Toseland, P. A., and Cameron, J. S.: Pulmonary tuberculosis in patient on 2:283-284,1968. hemodialysis. Brit. Med. J., 2:283-284, 1968. 19. Osborn, E. C., Jerums, G., and JuPP, B. A.: Blood angiotensinase activity in relation to the breakdown of angiotensin 11 II amide and nonisotopic phenylthiocarbamyl angiotensin II amide in hypertensive and normotensive patients. Cardiovasc. Res., 2:33-38,1968. 2 :33-38, 1968. 20. Prescott, L. F.: The metabolism of phenacetin in patients with renal disease. Clin. Pharmacol. Ther., 10:383-394, 1969. 21. Reidenberg, M. M.: Effect of kidney disease on pharmacokinetics and drug response. Proc. 3:174-181,1972. 5th Int. Congr. Pharmacology, 3:174-181, 1972. 22. Reidenberg, M. M.: Renal Function and Drug Action. Philadelphia, W. B. Saunders Co., 1971. 23. Reidenberg, M. M., James, M., and Dring, L. G.: The rate of procaine hydrolysis in serum of normal subjects and diseased patients. Clin. Pharmacol. Ther., 13:279-284, 13 :279-284, 1972. 24. Reidenberg, M. M., Kostenbauder, H., and Adams, W.: The rate of drug metabolism in obese volunteers before and during starvation and in azotemic patients. Metabolism, 18 :209-213, 1969. 25. Reidenberg, M. M., Shear, L., and Cohen, R. V.: Isoniazid elimination in patients with impaired renal function. Amer. Rev. Respir. Dis., 108:1426-1428, 1973. Departments of Pharmacology and Medicine Temple University School of Medicine Philadelphia, Pennsylvania 19140