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HIGH PLASMA CONCENTRATIONS OF β-RECEPTOR BLOCKING DRUGS AND DEFICIENT DEBRISOQUINE HYDROXYLATION
333
Letters
to
the Editor
HIGH PLASMA CONCENTRATIONS OF &bgr;-RECEPTOR BLOCKING DRUGS AND DEFICIENT DEBRISOQUINE HYDROXYLATION
SIR,-Several g-receptor blocking drugs, including alprenolol, metoprolol, and timolol, have been evaluated in the prevention of on recurrences after myocardial infarction. In the Norwegian which is timolol 3% of the patients dropped out due to bradycardia,study, a concentration dependent side effect. All three drugs are metabolised by oxidative pathways and steady-state plasma concentrations (after oral administration) will be determined largely by the activity of the enzymes involved. Genetically determined variability in drug oxidation between individuals is now well recognised and it has recently been shown that polymorphisms exist in drug oxidation; the most well known example is the hydroxylation of debrisoquine which is poor in a small proportion of northern Europeans. The phenotype can be determined by measuring the ratio between debrisoquine and its 4-hydroxylated metabolite in the urine after a small single oral dose.2 In pharmacokinetic studies of 0-blockers unusually high plasma concentrations have been found in a few subjects. We have phenotyped four individuals with unusually high plasma concentrations of alprenolol, metoprolol, or timolol, on the hypothesis that they might be poor debrisoquine hydroxylators. A 40-year-old patient received alprenolol 400 mg twice daily and then timolol 10 mg twice daily.3 Plasma concentrations 12 h after the last dose were 570 ng/ml (alprenolol) and 85 ng/ml (timolol) while in the other nineteen patients who took alprenolol, concentrations never exceeded 74 ng/ml and in twenty-nine patients on timolol, concentrations never exceeded 30 ng/ml. A 50-year-old patient (B:4 in our other study 4), treated with alprenolol 400 mg twice daily, had high plasma concentrations of the parent drug (115 ng/ml), and in contrast to what is usually observed, no 4-hydroxyalprenolol in his plasma. Two 25-year-old healthy male volunteers had high plasma concentrations, as judged by the area h after a under the plasma-concentration/time curve single oral dose of 100 mg alprenolol and 76 ng ml- h after a single oral dose of 50 mg metoprolol (subject C.G.H .5These values are about five times the average. The debrisoquine tests were done after treatment when the /3-blockers had been stopped. All were poor hydroxylators, with metabolic ratios of 30 or more (figure). It thus appears that poor metabolism of these three 0-blockers and debrisoquine are associated. Debrisoquine6 and alprenolol and metoprolol7,8are metabolised by mixed function oxidases in the liver. Possibly one cytochrome P-450 isozyme is either missing or functionally abnormal in poor metabolisers of debrisoquine.
of 63 ny ml-
Debrisoquine metabolic ratios in four subjects (<’) with high plasma concentrations of &bgr;-blockers. Ratios in 155 healthy Swedish volunteers are shown for comparison; 9 individuals with ratios above 12-66 are poor
hydroxylators.
Our findings show that a small proportion of patients are likely to have unusually high plasma concentrations on conventional 3-blocker dosage regimens and thus be at risk of concentration dependent side-effects such as unacceptable bradycardia. Such patients should be titrated clinically towards the smallest possible dose, and their overall drug therapy should be planned on the premise that they may be poor drug hydroxylators, which is easily tested. GUNNAR ALVAN Departments of Clinical CHRISTER VON BAHR Pharmacology and Medicine, PETER SEIDEMAN Karolinska Institute at Huddinge Hospital, FOLKE SJÖQVIST S-141 86 Huddinge, Sweden -
-
PROBABILITY OF MYELOMA IN PATIENTS WITH LOW ANION GAP
SIR,-In clinical teaching it is often claimed that a low anion gap is suggestive of multiple myeloma. I have tried to calculate, with Bayes’ theorem, the probability of myeloma in patients with a low anion gap-i.e., less than minus 2 SD from the normal mean of
([Na++K+]-[Cl-+HC03 ]). Hypoalbuminaemia and hyponatraemia are the main causes of a low anion gap; a significantly low anion gap is usually found in IgG myeloma, with its cationic paraproteins, and not in IgA myeloma, with its anionic paraproteins. 1,2The ratio of IgG to IgA myeloma is about 2- 5:1,3 so myeloma can contribute significantly to the population of low anion gaps found in a teaching hospital with a large oncology service, but probably less so in the community setting.
1. The Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981; 304: 801-07. 2. Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL. Polymorphic hydroxylation of debrisoquine in man. Lancet 1977; ii: 584-86. 3. Maren N, Alvan G, Calissendorff BM, Haglund K, Seideman P. Additive intraocular pressure reducing effect of topical timolol during systemic &bgr;-blockade. Acta Ophthalmol Scand (in press). 4. Seideman P, Grahnén A, Haglund K, Lindström B, von Bahr C Prazosin first dose phenomenon during combined treatment with a &bgr;-blocker in hypertensive patients. Br J Clin Pharmacol (in press). 5 Jordö L, Attman PO, Aurell M, Johansson L, Johnsson G, Regårdh C-G. Pharmacokinetic and pharmacodynamic properties of metoprolol in patients with impaired renal function. Clin Pharmacokinet 1980; 5: 169-80. 6. Davies DS, Kahn GC, Murray S, Brodie MJ, Boobis AR; Evidence for an enzymatic defect in the 4-hydroxylation of debrisoquine by human liver. Br J Clin Pharmacol 1981, 11: 89-91. 7 Grundin R, Moldéus P, Orrenius S, Skånberg I, von Bahr C. The possible role of cytochrome P-450 in the liver "first pass elimination ofa &bgr;-receptor blocking drug. Acta Pharmacol Toxicol 1974, 35: 242-60 8. Borg K-O, Carlsson E, Hoffmann K-J, Jönsson T-E, Thorin H, Wallin B. Metabolism of metoprolol-(3H) in man, the dog and the rat. Acta Pharmacol Toxicol 1975; 36:
(suppl V)
125-35.
DA, Mahgoub A, Sloan TP, Idle JR, Smith RL. A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population J Med Genet 1980; 17: 102-05.
9 Price Evans
The calculation
uses
the
expression:
P(DIS)P(D)xP(SID) P(S) of multiple myeloma if a patient has a low anion gap (as defined) probability of multiple myeloma in the general
P(D S)= probability P(D)
=
population of demonstrating a low anion gap population of patients with confirmed multiple myeloma probability of a low anion gap in the general hospital population
P(SD)=probability in
P(S)
=
a
P(D), P(S D) and P(S) can be found or extrapolated from previous on multiple myeloma and the anion gap.
studies
1. DeTroyer A, Stolarczyk A, deBeyl DZ, Stryckmans P. Value of anion determination in multiple myeloma. N Engl J Med 1977; 296: 858-60.
gap
2. Paladini G, Sala PG. Anion gap in multiple myeloma. Acta Haematol 1979; 62: 148-52. 3. Bakemeier RF, Cooper RA, Rubin P. The malignant lymphomas, multiple myeloma, and macroglobulinemia. In: Clinical oncology for medical students and physicians. American Cancer Society Publishing, 1978: 239.
Letters
to
the Editor
HIGH PLASMA CONCENTRATIONS OF &bgr;-RECEPTOR BLOCKING DRUGS AND DEFICIENT DEBRISOQUINE HYDROXYLATION
SIR,-Several g-receptor blocking drugs, including alprenolol, metoprolol, and timolol, have been evaluated in the prevention of on recurrences after myocardial infarction. In the Norwegian which is timolol 3% of the patients dropped out due to bradycardia,study, a concentration dependent side effect. All three drugs are metabolised by oxidative pathways and steady-state plasma concentrations (after oral administration) will be determined largely by the activity of the enzymes involved. Genetically determined variability in drug oxidation between individuals is now well recognised and it has recently been shown that polymorphisms exist in drug oxidation; the most well known example is the hydroxylation of debrisoquine which is poor in a small proportion of northern Europeans. The phenotype can be determined by measuring the ratio between debrisoquine and its 4-hydroxylated metabolite in the urine after a small single oral dose.2 In pharmacokinetic studies of 0-blockers unusually high plasma concentrations have been found in a few subjects. We have phenotyped four individuals with unusually high plasma concentrations of alprenolol, metoprolol, or timolol, on the hypothesis that they might be poor debrisoquine hydroxylators. A 40-year-old patient received alprenolol 400 mg twice daily and then timolol 10 mg twice daily.3 Plasma concentrations 12 h after the last dose were 570 ng/ml (alprenolol) and 85 ng/ml (timolol) while in the other nineteen patients who took alprenolol, concentrations never exceeded 74 ng/ml and in twenty-nine patients on timolol, concentrations never exceeded 30 ng/ml. A 50-year-old patient (B:4 in our other study 4), treated with alprenolol 400 mg twice daily, had high plasma concentrations of the parent drug (115 ng/ml), and in contrast to what is usually observed, no 4-hydroxyalprenolol in his plasma. Two 25-year-old healthy male volunteers had high plasma concentrations, as judged by the area h after a under the plasma-concentration/time curve single oral dose of 100 mg alprenolol and 76 ng ml- h after a single oral dose of 50 mg metoprolol (subject C.G.H .5These values are about five times the average. The debrisoquine tests were done after treatment when the /3-blockers had been stopped. All were poor hydroxylators, with metabolic ratios of 30 or more (figure). It thus appears that poor metabolism of these three 0-blockers and debrisoquine are associated. Debrisoquine6 and alprenolol and metoprolol7,8are metabolised by mixed function oxidases in the liver. Possibly one cytochrome P-450 isozyme is either missing or functionally abnormal in poor metabolisers of debrisoquine.
of 63 ny ml-
Debrisoquine metabolic ratios in four subjects (<’) with high plasma concentrations of &bgr;-blockers. Ratios in 155 healthy Swedish volunteers are shown for comparison; 9 individuals with ratios above 12-66 are poor
hydroxylators.
Our findings show that a small proportion of patients are likely to have unusually high plasma concentrations on conventional 3-blocker dosage regimens and thus be at risk of concentration dependent side-effects such as unacceptable bradycardia. Such patients should be titrated clinically towards the smallest possible dose, and their overall drug therapy should be planned on the premise that they may be poor drug hydroxylators, which is easily tested. GUNNAR ALVAN Departments of Clinical CHRISTER VON BAHR Pharmacology and Medicine, PETER SEIDEMAN Karolinska Institute at Huddinge Hospital, FOLKE SJÖQVIST S-141 86 Huddinge, Sweden -
-
PROBABILITY OF MYELOMA IN PATIENTS WITH LOW ANION GAP
SIR,-In clinical teaching it is often claimed that a low anion gap is suggestive of multiple myeloma. I have tried to calculate, with Bayes’ theorem, the probability of myeloma in patients with a low anion gap-i.e., less than minus 2 SD from the normal mean of
([Na++K+]-[Cl-+HC03 ]). Hypoalbuminaemia and hyponatraemia are the main causes of a low anion gap; a significantly low anion gap is usually found in IgG myeloma, with its cationic paraproteins, and not in IgA myeloma, with its anionic paraproteins. 1,2The ratio of IgG to IgA myeloma is about 2- 5:1,3 so myeloma can contribute significantly to the population of low anion gaps found in a teaching hospital with a large oncology service, but probably less so in the community setting.
1. The Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981; 304: 801-07. 2. Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL. Polymorphic hydroxylation of debrisoquine in man. Lancet 1977; ii: 584-86. 3. Maren N, Alvan G, Calissendorff BM, Haglund K, Seideman P. Additive intraocular pressure reducing effect of topical timolol during systemic &bgr;-blockade. Acta Ophthalmol Scand (in press). 4. Seideman P, Grahnén A, Haglund K, Lindström B, von Bahr C Prazosin first dose phenomenon during combined treatment with a &bgr;-blocker in hypertensive patients. Br J Clin Pharmacol (in press). 5 Jordö L, Attman PO, Aurell M, Johansson L, Johnsson G, Regårdh C-G. Pharmacokinetic and pharmacodynamic properties of metoprolol in patients with impaired renal function. Clin Pharmacokinet 1980; 5: 169-80. 6. Davies DS, Kahn GC, Murray S, Brodie MJ, Boobis AR; Evidence for an enzymatic defect in the 4-hydroxylation of debrisoquine by human liver. Br J Clin Pharmacol 1981, 11: 89-91. 7 Grundin R, Moldéus P, Orrenius S, Skånberg I, von Bahr C. The possible role of cytochrome P-450 in the liver "first pass elimination ofa &bgr;-receptor blocking drug. Acta Pharmacol Toxicol 1974, 35: 242-60 8. Borg K-O, Carlsson E, Hoffmann K-J, Jönsson T-E, Thorin H, Wallin B. Metabolism of metoprolol-(3H) in man, the dog and the rat. Acta Pharmacol Toxicol 1975; 36:
(suppl V)
125-35.
DA, Mahgoub A, Sloan TP, Idle JR, Smith RL. A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population J Med Genet 1980; 17: 102-05.
9 Price Evans
The calculation
uses
the
expression:
P(DIS)P(D)xP(SID) P(S) of multiple myeloma if a patient has a low anion gap (as defined) probability of multiple myeloma in the general
P(D S)= probability P(D)
=
population of demonstrating a low anion gap population of patients with confirmed multiple myeloma probability of a low anion gap in the general hospital population
P(SD)=probability in
P(S)
=
a
P(D), P(S D) and P(S) can be found or extrapolated from previous on multiple myeloma and the anion gap.
studies
1. DeTroyer A, Stolarczyk A, deBeyl DZ, Stryckmans P. Value of anion determination in multiple myeloma. N Engl J Med 1977; 296: 858-60.
gap
2. Paladini G, Sala PG. Anion gap in multiple myeloma. Acta Haematol 1979; 62: 148-52. 3. Bakemeier RF, Cooper RA, Rubin P. The malignant lymphomas, multiple myeloma, and macroglobulinemia. In: Clinical oncology for medical students and physicians. American Cancer Society Publishing, 1978: 239.