- Email: [email protected]
POLYMORPHIC HYDROXYLATION OF DEBRISOQUINE
718 blood. Oxyhaemoglobin remains red.’1
turns
brown; carboxyhaemoglobin
4400 Prince
Road, Rockville, Maryland 20853, U.S.A.
BRUCE T. ADORNATO
POLYMORPHIC HYDROXYLATION OF
DEBRISOQUINE SIR,-Dr Mahgoub and his colleagues (Sept. 17, p. 584) report that the ratio of the urinary recovery of unchanged debrisoquine (D) to that of its 4-hydroxy metabolite (4HD) was bimodally distributed in volunteers, indicating genetic polymorphism in this oxidative pathway. Our findings in 51 patients on continuous debrisoquine therapy (5-160 mg twice a day) support this conclusion. The ratio D/4HD recovery was determined in 24 h urine collections by gas chromatography.2 Our data for 30 outpatients and 21 inpatients are shown in the figure, together with those of Mahgoub et al., bringing the total frequency of to 7%. Continuous dosage "poor metabolisers" (D/4HD>21) tends to increase D/4HD ratios compared with those observed after single doses; as a result of saturation and/or inhibition of
4-hydroxylation.33 Data from
quine twice
a
’
compliant inpatients receiving 5-40 mg debrisoday further indicated that significantly more of
1.
Koch-Weser, J. in Harrison’s Principles of Internal Medicine; p. 694. New York, 1977. 2. Lennard, M. S., Silas, J. H., Smith, A. J., Tucker, G. T. J. Chromatogr. 1977, 133, 161. 3. Silas, J. H., Lennard, M. S., Tucker, G. T., Smith, A. J., Malcolm, S. L., Marten, T. R. Br.J. clin. Pharmac. (in the press).
the dose was unaccounted for as D+4HD in those with D/4HD ratios below 5 (n=16) than in those with ratios above Since debri21 (n=5) (SS±9%s.D. v. 19±12% s.D.; r<0001). than is 75%* and soquine absorption consistently greater since production of phenolic metabolites seems to be independent of 4-hydroxylator status (Mahgoub et al.) formation of the remaining known metabolites-namely, ring-opened carboxylic acids’-may also be deficient in those who do not produce much 4HD. These acids are probably formed via 1 and 3 hydroxy compounds which, like 4HD, would arise from ali-
cyclic hydroxylation. Antipyrine, often used as a model substrate in drug-metabolism studies, also undergoes alicyclic 4-hydroxylation as a major metabolic conversion.’Furthermore, Kellermann et al.8e have observed three distinct groups in a selected homogeneous population with respect to metabolism of the compound. However, we found no correlation between the ability to 4-hydroxylate debrisoquine and antipyrine clearance in 6 patients. 3 patients with D/4HD ratios between 25 and 44 had antipyrine clearances of 0.40-1.33 ml kg-lmin-land 3 with D/4HD ratios between 0.33 and 0.66 had antipyrine clearances of 0.64-0-88 ml krlmin-1. This finding might be anticipated since the 4-carbon of antipyrine is linked in a double-bond and the mechanism of hydroxylation, via epoxide-diol formation,9 is likely to differ from that of debrisoquine. We have also investigated the possibility thatdebrisoquine might be a substrate for dopamine &bgr;-hydroxylase. However, no 4-hydroxy debrisoquine was detected after incubation with the enzyme at pH 5 and 370C for 1 h. G. T. TUCKER Section of Therapeutics, Academic Division of Medicine,
University of Sheffield, Royal Infirmary, Sheffield S6 3DA
J. H. SILAS A. O. IYUN M. S. LENNARD
A. J. SMITH
DRUG TRIALS: ALLOWING FOR COST
SIR,-Your editorial of Sept. 17 (p. 595) misunderstands work.’ The underlying concept is this. The null hypothesis that there is no difference between, let us say, two drug treatments A and B. In ordinary circumstances an investigator only asks "was there a difference in either direction?" Consider for the moment only the type I error (a) which is the our
assumes
risk of finding a difference when none exists. Most biological scientists have accepted a 5% (0.05) risk as their cut-off point for statistical significance. If there is a possibility that A could be either better or worse than B the risk is divided into two tails which are commonly set at 2.5% (0-025) each. However, real life is seldom so simple. The implications of finding that A is better than B may be quite different from the converse, If, for example, the adoption of drug A carried with it some disadvantage to the patient, such as a greater chance of adverse reaction, or increased cost, most people would wish to be more sure of their findings than if the result of the trial was the other way round. They should therefore choose different values of ex for each of the two tails. We are not abandoning or bending the null hypothesis as you suggest, but only saying that, whether we like it or not, our choice of a is the risk that we take of making a false decision. So it is better to select it deliberately to take into 4.
5. 6.
1976, 3, 332. Brodie, B. B., Axelrod, J.J. Pharmac. 1950, 98, 97. 8. Kellermann, G , Luyten-Kellerman, M., Horning, M. G., Stafford, M. Clin. Pharmac. Ther. 1976, 20, 72. 9. Stafford, M., Kellerman, G., Stillwell, R. N., Horning, M. G. Res. Comm. chem. Path. Pharmac. 1974, 8, 593. 1. Chaput de Saintonge, D. M., Vere, D. W., Sharman, V. L. Br. J. clin. Pharmac. 1977, 4, 411. 7.
Frequency distribution of the ratio, urinary debrisoquine/4-hydroxydebrisoquine, in 145 subjects.
Angelo, M., Dring, L. G., Lancaster, R., Smith, R. L. Biochem. Soc. Trans 1976, 4, 704. Iyun, A. O., Silas, J. H., Smith, A. J., Tucker, G. T. Unpublished. Allen, J. G., East, P. B., Francis, R. J., Haigh, J. L. Drug Metab. Dispos.
turns
brown; carboxyhaemoglobin
4400 Prince
Road, Rockville, Maryland 20853, U.S.A.
BRUCE T. ADORNATO
POLYMORPHIC HYDROXYLATION OF
DEBRISOQUINE SIR,-Dr Mahgoub and his colleagues (Sept. 17, p. 584) report that the ratio of the urinary recovery of unchanged debrisoquine (D) to that of its 4-hydroxy metabolite (4HD) was bimodally distributed in volunteers, indicating genetic polymorphism in this oxidative pathway. Our findings in 51 patients on continuous debrisoquine therapy (5-160 mg twice a day) support this conclusion. The ratio D/4HD recovery was determined in 24 h urine collections by gas chromatography.2 Our data for 30 outpatients and 21 inpatients are shown in the figure, together with those of Mahgoub et al., bringing the total frequency of to 7%. Continuous dosage "poor metabolisers" (D/4HD>21) tends to increase D/4HD ratios compared with those observed after single doses; as a result of saturation and/or inhibition of
4-hydroxylation.33 Data from
quine twice
a
’
compliant inpatients receiving 5-40 mg debrisoday further indicated that significantly more of
1.
Koch-Weser, J. in Harrison’s Principles of Internal Medicine; p. 694. New York, 1977. 2. Lennard, M. S., Silas, J. H., Smith, A. J., Tucker, G. T. J. Chromatogr. 1977, 133, 161. 3. Silas, J. H., Lennard, M. S., Tucker, G. T., Smith, A. J., Malcolm, S. L., Marten, T. R. Br.J. clin. Pharmac. (in the press).
the dose was unaccounted for as D+4HD in those with D/4HD ratios below 5 (n=16) than in those with ratios above Since debri21 (n=5) (SS±9%s.D. v. 19±12% s.D.; r<0001). than is 75%* and soquine absorption consistently greater since production of phenolic metabolites seems to be independent of 4-hydroxylator status (Mahgoub et al.) formation of the remaining known metabolites-namely, ring-opened carboxylic acids’-may also be deficient in those who do not produce much 4HD. These acids are probably formed via 1 and 3 hydroxy compounds which, like 4HD, would arise from ali-
cyclic hydroxylation. Antipyrine, often used as a model substrate in drug-metabolism studies, also undergoes alicyclic 4-hydroxylation as a major metabolic conversion.’Furthermore, Kellermann et al.8e have observed three distinct groups in a selected homogeneous population with respect to metabolism of the compound. However, we found no correlation between the ability to 4-hydroxylate debrisoquine and antipyrine clearance in 6 patients. 3 patients with D/4HD ratios between 25 and 44 had antipyrine clearances of 0.40-1.33 ml kg-lmin-land 3 with D/4HD ratios between 0.33 and 0.66 had antipyrine clearances of 0.64-0-88 ml krlmin-1. This finding might be anticipated since the 4-carbon of antipyrine is linked in a double-bond and the mechanism of hydroxylation, via epoxide-diol formation,9 is likely to differ from that of debrisoquine. We have also investigated the possibility thatdebrisoquine might be a substrate for dopamine &bgr;-hydroxylase. However, no 4-hydroxy debrisoquine was detected after incubation with the enzyme at pH 5 and 370C for 1 h. G. T. TUCKER Section of Therapeutics, Academic Division of Medicine,
University of Sheffield, Royal Infirmary, Sheffield S6 3DA
J. H. SILAS A. O. IYUN M. S. LENNARD
A. J. SMITH
DRUG TRIALS: ALLOWING FOR COST
SIR,-Your editorial of Sept. 17 (p. 595) misunderstands work.’ The underlying concept is this. The null hypothesis that there is no difference between, let us say, two drug treatments A and B. In ordinary circumstances an investigator only asks "was there a difference in either direction?" Consider for the moment only the type I error (a) which is the our
assumes
risk of finding a difference when none exists. Most biological scientists have accepted a 5% (0.05) risk as their cut-off point for statistical significance. If there is a possibility that A could be either better or worse than B the risk is divided into two tails which are commonly set at 2.5% (0-025) each. However, real life is seldom so simple. The implications of finding that A is better than B may be quite different from the converse, If, for example, the adoption of drug A carried with it some disadvantage to the patient, such as a greater chance of adverse reaction, or increased cost, most people would wish to be more sure of their findings than if the result of the trial was the other way round. They should therefore choose different values of ex for each of the two tails. We are not abandoning or bending the null hypothesis as you suggest, but only saying that, whether we like it or not, our choice of a is the risk that we take of making a false decision. So it is better to select it deliberately to take into 4.
5. 6.
1976, 3, 332. Brodie, B. B., Axelrod, J.J. Pharmac. 1950, 98, 97. 8. Kellermann, G , Luyten-Kellerman, M., Horning, M. G., Stafford, M. Clin. Pharmac. Ther. 1976, 20, 72. 9. Stafford, M., Kellerman, G., Stillwell, R. N., Horning, M. G. Res. Comm. chem. Path. Pharmac. 1974, 8, 593. 1. Chaput de Saintonge, D. M., Vere, D. W., Sharman, V. L. Br. J. clin. Pharmac. 1977, 4, 411. 7.
Frequency distribution of the ratio, urinary debrisoquine/4-hydroxydebrisoquine, in 145 subjects.
Angelo, M., Dring, L. G., Lancaster, R., Smith, R. L. Biochem. Soc. Trans 1976, 4, 704. Iyun, A. O., Silas, J. H., Smith, A. J., Tucker, G. T. Unpublished. Allen, J. G., East, P. B., Francis, R. J., Haigh, J. L. Drug Metab. Dispos.