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METHOXYPHENAMINE AND DEXTROMETHORPHAN AS SAFE PROBES FOR DEBRISOQUINE HYDROXYLATION POLYMORPHISM
1393 109 mm Hg on Aug 3. Mechanical ventilation was discontinued the following day. This patient had disorder in many body systems after treatment for advanced testicular tumour. The respiratory component of his
DRUG AND METABOLITE EXCRETION AFTER
60. mg
METHOXYPHENAMINE HYDROCHLORIDE ORALLY TO FIVE HEALTHY VOLUNTEERS
illness worsened considerably at the same time as first monocytes and then neutrophils started to appear in his peripheral blood-a sequence of events consistent with the hypothesis that ARDS results from neutrophil products. A further pointer in this direction is the impression that some neutropenic patients may have radiologically severe changes in the lungs and yet be free of respiratory distress. This problem is not common, but when it does occur prospective monitoring of these patients may permit further investigation of ARDS; and recovery from cytotoxic drug induced neutropenia is a possible approach by which experimental pathologists may examine its mechanism. Cross Hospital, London W6 8RF
Charing
1. Thommasen
with adult
S. M. CRAWFORD
HV, Russell JA, Boyko WJ, Hogg JC Transient leucopenia associated respiratory distress syndrome Lancet 1984, i. 809-12.
METHOXYPHENAMINE AND DEXTROMETHORPHAN AS SAFE PROBES FOR DEBRISOQUINE HYDROXYLATION POLYMORPHISM
SiR,—Dr Kupfer and others (Sept 1, p 517) suggest dextromethorphan as a safe probe for assessing debrisoquine-type drug hydroxylation polymorphism. We too have investigated interphenotype differences in the handling of a component of cough syrups-namely, methoxyphenamine (MP), a 02-adrenergic stimulant that is metabolised by three distinct metabolic pathways 1 (aromatic hydroxylation, N-demethylation, and O-demethylation).1 60’ 3 mg methoxyphenamine hydrochloride was given by mouth to healthy volunteers who were poor (three) or extensive (eight) hydroxylators of debrisoquine. Samples of the 0-12 h urine were hydrolysed with sulphatase/glucuronidase and analysed for MP and the three metabolites.2No interphenotype differences for the N-demethyl metabolite were found. However, there were significant differences in the urinary excretion of hydroxymethoxyphenamine (OHMP) and O-demethylMP and in the urinary metabolic ratios of MP to either of these two metabolites. A highly significant correlation was found between the debrisoquine metabolic ratio and either of the MP metabolic ratios, as shown (figure) for the MP/O-demethylMP ratio. Thus, both the aromatic hydroxylation and the O-demethylation of MP are likely coinherited with determined genetically debrisoquine
hydroxylation. Dextromethorphan (pKa 8’3)3 and MP (pKa 10’45)4 are basic drugs, where the excretion of drug and many non-conjugated metabolites retaining the basic centre is dependent upon the urinary pH. However, the excretion of a metabolite largely eliminated in the urine as conjugates is pH independent. Thus, a metabolic ratio expressed in terms of a parent drug and this latter type of metabolite will be affected by urine pH. This has an important implication in
that an individual phenotyped by such a metabolic ratio on two different occasions may give widely different results. MP was orally administered to five healthy volunteers on two separate occasions under controlled acidic and alkaline conditions. The renal excretions of MP, O-demethylMP, and N-demethylMP were pH dependent, while OHMP excretion was independent of pH (table). Thus, metabolic ratios based on OHMP, a metabolite largely (>70%) excreted as glucuronide and/or sulphate conjugates, are affected by urine pH. On the other hand, O-demethylMP is and the MP/0largely excreted non-conjugated (>90%), demethylMP metabolic ratio is not appreciably affected by changes in urine pH. Thus, the relatively innocuous agent methoxyphenamine can be used reliably to assess genetic drug hydroxylation
phenotype. Since the 0-demethyl and N,O-didemethyl metabolites of dextromethorphan are largely excreted as conjugates,5 it is likely that metabolic ratios based on parent drug to either of these metabolites will be affected by changes in renal pH. Therefore, it is necessary to ensure that renal pH will not affect phenotype status before recommending dextromethorphan as a safe probe of debrisoquinetype drug hydroxylation polymorphism.
Supported by Medical
Research Council of Canada, MA-8673.
College of Pharmacy, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N
0W0
S. D. ROY E. M. HAWES J. W. HUBBARD G. MCKAY K. K. MIDHA
1. Midha
KK, Cooper JK, McGilveray IJ, Coutts RT, Dawe R. Metabolism ofmethoxyphenamine in man and in monkey. Drug Metab Dispos 1976; 4: 568-76 2. Roy SD, Hawes EM, McKay G, Hubbard JW, Midha KK Methoxyphenamine metabolism in rat models of human debrisoquine phenotypes. Can J Physiol Pharmacol (in press) 3. Newton DW, Kluza RB. pKa values of medicinal compounds in pharmacy practice. Drug Intell Clin Pharm 1978; 12: 546-54. 4 Warren RJ, Begosh PP, Zarembo JE Identification of amphetamines and related sympathomimetic amines. J Assoc Off Analyt Chem 1971; 54: 1179-91. 5 Barnhart JW The urinary excretion of dextromethorphan and three metabolites in dogs and humans Toxicol Appl Pharmacol 1980, 55: 43-48.
AFLATOXIN, HEPATOCELLULAR CARCINOMA, AND SCHISTOSOMIASIS
SIR,-In his hypothesis linking aflatoxin with hepatocellular
Debrisoquine/4-hydroxydebrisoquine
(MRDEB) and methoxyphenamine/0-demethylmethoxyphenamine metabolic ratios (MRMP) in three poor (8) and eight extensive metaboliser phenotypes (0) of debrisoquine hydroxylation (p
carcinoma (HCC) Dr Enwonwu (Oct 27, p 957) invokes parasitic infection with schistosomes as a co-factor in hepatic carcinogenesis. However, he is incorrect in suggesting that schistosomiasis "acts by stimulating a hyperplastic response of the liver, thus rendering it more vulnerable to malignant transformation by ingested chemicalcarcinogens". Liver injury in Schistosoma mansonz and S japonicum infections is confined to fibrosis of portal tracts: so-called Symmers’ pipestem fibrosis.’ The hepatic parenchyma is unaffected, apart from some increase in collagen in the space ofDisse. The result is an alteration of hepatic haemodynamics without a change in hepatocellular function, which is well preserved until the very late stages of the disease. There is no "hyperplastic response". In murine schistosomiasis mixed function oxidase (MFO) enzyme activity is depressed2 and in compensated human schistosomiasis,3 drug-metabolising activity is decreased, at least in Brazilians.3 Therefore schistosomiasis per se is unlikely to render the liver
DRUG AND METABOLITE EXCRETION AFTER
60. mg
METHOXYPHENAMINE HYDROCHLORIDE ORALLY TO FIVE HEALTHY VOLUNTEERS
illness worsened considerably at the same time as first monocytes and then neutrophils started to appear in his peripheral blood-a sequence of events consistent with the hypothesis that ARDS results from neutrophil products. A further pointer in this direction is the impression that some neutropenic patients may have radiologically severe changes in the lungs and yet be free of respiratory distress. This problem is not common, but when it does occur prospective monitoring of these patients may permit further investigation of ARDS; and recovery from cytotoxic drug induced neutropenia is a possible approach by which experimental pathologists may examine its mechanism. Cross Hospital, London W6 8RF
Charing
1. Thommasen
with adult
S. M. CRAWFORD
HV, Russell JA, Boyko WJ, Hogg JC Transient leucopenia associated respiratory distress syndrome Lancet 1984, i. 809-12.
METHOXYPHENAMINE AND DEXTROMETHORPHAN AS SAFE PROBES FOR DEBRISOQUINE HYDROXYLATION POLYMORPHISM
SiR,—Dr Kupfer and others (Sept 1, p 517) suggest dextromethorphan as a safe probe for assessing debrisoquine-type drug hydroxylation polymorphism. We too have investigated interphenotype differences in the handling of a component of cough syrups-namely, methoxyphenamine (MP), a 02-adrenergic stimulant that is metabolised by three distinct metabolic pathways 1 (aromatic hydroxylation, N-demethylation, and O-demethylation).1 60’ 3 mg methoxyphenamine hydrochloride was given by mouth to healthy volunteers who were poor (three) or extensive (eight) hydroxylators of debrisoquine. Samples of the 0-12 h urine were hydrolysed with sulphatase/glucuronidase and analysed for MP and the three metabolites.2No interphenotype differences for the N-demethyl metabolite were found. However, there were significant differences in the urinary excretion of hydroxymethoxyphenamine (OHMP) and O-demethylMP and in the urinary metabolic ratios of MP to either of these two metabolites. A highly significant correlation was found between the debrisoquine metabolic ratio and either of the MP metabolic ratios, as shown (figure) for the MP/O-demethylMP ratio. Thus, both the aromatic hydroxylation and the O-demethylation of MP are likely coinherited with determined genetically debrisoquine
hydroxylation. Dextromethorphan (pKa 8’3)3 and MP (pKa 10’45)4 are basic drugs, where the excretion of drug and many non-conjugated metabolites retaining the basic centre is dependent upon the urinary pH. However, the excretion of a metabolite largely eliminated in the urine as conjugates is pH independent. Thus, a metabolic ratio expressed in terms of a parent drug and this latter type of metabolite will be affected by urine pH. This has an important implication in
that an individual phenotyped by such a metabolic ratio on two different occasions may give widely different results. MP was orally administered to five healthy volunteers on two separate occasions under controlled acidic and alkaline conditions. The renal excretions of MP, O-demethylMP, and N-demethylMP were pH dependent, while OHMP excretion was independent of pH (table). Thus, metabolic ratios based on OHMP, a metabolite largely (>70%) excreted as glucuronide and/or sulphate conjugates, are affected by urine pH. On the other hand, O-demethylMP is and the MP/0largely excreted non-conjugated (>90%), demethylMP metabolic ratio is not appreciably affected by changes in urine pH. Thus, the relatively innocuous agent methoxyphenamine can be used reliably to assess genetic drug hydroxylation
phenotype. Since the 0-demethyl and N,O-didemethyl metabolites of dextromethorphan are largely excreted as conjugates,5 it is likely that metabolic ratios based on parent drug to either of these metabolites will be affected by changes in renal pH. Therefore, it is necessary to ensure that renal pH will not affect phenotype status before recommending dextromethorphan as a safe probe of debrisoquinetype drug hydroxylation polymorphism.
Supported by Medical
Research Council of Canada, MA-8673.
College of Pharmacy, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N
0W0
S. D. ROY E. M. HAWES J. W. HUBBARD G. MCKAY K. K. MIDHA
1. Midha
KK, Cooper JK, McGilveray IJ, Coutts RT, Dawe R. Metabolism ofmethoxyphenamine in man and in monkey. Drug Metab Dispos 1976; 4: 568-76 2. Roy SD, Hawes EM, McKay G, Hubbard JW, Midha KK Methoxyphenamine metabolism in rat models of human debrisoquine phenotypes. Can J Physiol Pharmacol (in press) 3. Newton DW, Kluza RB. pKa values of medicinal compounds in pharmacy practice. Drug Intell Clin Pharm 1978; 12: 546-54. 4 Warren RJ, Begosh PP, Zarembo JE Identification of amphetamines and related sympathomimetic amines. J Assoc Off Analyt Chem 1971; 54: 1179-91. 5 Barnhart JW The urinary excretion of dextromethorphan and three metabolites in dogs and humans Toxicol Appl Pharmacol 1980, 55: 43-48.
AFLATOXIN, HEPATOCELLULAR CARCINOMA, AND SCHISTOSOMIASIS
SIR,-In his hypothesis linking aflatoxin with hepatocellular
Debrisoquine/4-hydroxydebrisoquine
(MRDEB) and methoxyphenamine/0-demethylmethoxyphenamine metabolic ratios (MRMP) in three poor (8) and eight extensive metaboliser phenotypes (0) of debrisoquine hydroxylation (p
carcinoma (HCC) Dr Enwonwu (Oct 27, p 957) invokes parasitic infection with schistosomes as a co-factor in hepatic carcinogenesis. However, he is incorrect in suggesting that schistosomiasis "acts by stimulating a hyperplastic response of the liver, thus rendering it more vulnerable to malignant transformation by ingested chemicalcarcinogens". Liver injury in Schistosoma mansonz and S japonicum infections is confined to fibrosis of portal tracts: so-called Symmers’ pipestem fibrosis.’ The hepatic parenchyma is unaffected, apart from some increase in collagen in the space ofDisse. The result is an alteration of hepatic haemodynamics without a change in hepatocellular function, which is well preserved until the very late stages of the disease. There is no "hyperplastic response". In murine schistosomiasis mixed function oxidase (MFO) enzyme activity is depressed2 and in compensated human schistosomiasis,3 drug-metabolising activity is decreased, at least in Brazilians.3 Therefore schistosomiasis per se is unlikely to render the liver