460P
PROCEEDINGS OF THE B.P.S., 13th-15th SEPTEMBER, 1978
POSTER COMMUNICATIONS Failure of 2 h [14C]-aminopyrine breath test to demonstrate microsomal enzyme induction by glutethimide G. SHARPE*2, G.D. BELL', S.T. CARTWRIGHT2, S. CHAPLIN*2 & D.A. HENRY1 (introduced by M.J.S. LANGMAN) Department of Therapeutics, City Hospital, Hucknall Road, Nottingham 2Nottingham University Medical School, Clifton Boulevard, Nottingham
The specific activity of 14C02 exhaled in the breath in the 2h following an oral dose of [14C]-labelled aminopyrine, ["4C]-aminopyrine breath test (ABT), is a convenient measure of hepatic microsomal demethylating capacity (Hepner & Vesell, 1976). Values for the ABT are reduced in the presence of liver disease (Galizzi, Long, Billing & Sherlock, 1978) and are increased in patients on chronic anticonvulsant therapy probably indicating hepatic microsomal induction (Hepner, Vesell, Lipton, Harvey, Wilkinson & Schenker, 1977). In our study an ABT was performed on five healthy volunteers before and after a 14 day course of glutethimide (500 mg/day), a drug known to cause enzyme induction (Corn, 1966). A tracer dose (1.5 gCi) of [14C]-aminopyrine was given orally in a fasting state. 14CO2, produced by hepatic demethylation of the drug, was collected by blowing into vials employing hyamine as a trapping agent. The vials were counted in a liquid scintillation counter and the specific activity of the 2 h breath sample was expressed as a percentage of the administered dose excreted in 2 h (ABT). The half life (Ti) of the decay of specific activity was calculated from at least four values obtained 2-6 h after administration of the drug. The following results were obtained:
ABT
(i) before glutethimide (ii) after glutethimide
Range (mean + s.d.) 7.5-12.6% (10.8 + 2.1) 9.4-13.2% (10.5 + 1.5)
T2 specific activity breath "4C02. (i) before glutethimide 106.9-137.8 min (126.6 + 11.6) (ii) after glutethimide 86.3-111.7 min (100.7* + 9.3) * P < 0.01 paired t-test. All five individuals demonstrated shortening of the Ti values following glutethimide treatment and in three cases studied there was also marked increase in urinary D-glucaric acid excretion. Thus there was clear evidence of induction of microsomal enzyme activity which was not reflected in a corresponding increase in the value for the ABT. We conclude that if the ["4C]-aminopyrine breath test is to be used as a screening test for drug induced microsomal induction, it is necessary to calculate the T, and not just simply take one sample at 2 h as has been previously suggested (Hepner & Vesell, 1976). References CORN, M. (1966). Effect of phenobarbital and glutethimide on biological half life of warfarin. Thromb. Diath. Haemorrh., 16, 606-612. GALIZZI, J., LONG, R.G., BILLING, B.H. & SHERLOCK, S.
(1978). Assessment of the [14C]-aminopyrine breath test in liver disease. Gut, 19, 40-45. HEPNER, G.W. & VESELL, E.S. (1976). Aminopyrine disposition: Studies on breath, saliva and urine of normal people and patients with liver disease. Clin. Pharmac. Ther., 20, 654-660. HEPNER, G.W., VESELL, E.S., LIPTON, A., HARVEY, H.A.,
WILKINSON, G.R. & SCHENKER, S. (1977). Disposition of aminopyrine, antipyrine, diazepam, and indocyanine green in patients with liver disease or on anticonvulsant drug therapy. Diazepam breath test and correlatives in drug elimination. J. lab. clin. Med., 90, 440-456.
PROCEEDINGS OF THE B.P.S., 13th-15th SEPTEMBER, 1978
POSTER COMMUNICATIONS Failure of 2 h [14C]-aminopyrine breath test to demonstrate microsomal enzyme induction by glutethimide G. SHARPE*2, G.D. BELL', S.T. CARTWRIGHT2, S. CHAPLIN*2 & D.A. HENRY1 (introduced by M.J.S. LANGMAN) Department of Therapeutics, City Hospital, Hucknall Road, Nottingham 2Nottingham University Medical School, Clifton Boulevard, Nottingham
The specific activity of 14C02 exhaled in the breath in the 2h following an oral dose of [14C]-labelled aminopyrine, ["4C]-aminopyrine breath test (ABT), is a convenient measure of hepatic microsomal demethylating capacity (Hepner & Vesell, 1976). Values for the ABT are reduced in the presence of liver disease (Galizzi, Long, Billing & Sherlock, 1978) and are increased in patients on chronic anticonvulsant therapy probably indicating hepatic microsomal induction (Hepner, Vesell, Lipton, Harvey, Wilkinson & Schenker, 1977). In our study an ABT was performed on five healthy volunteers before and after a 14 day course of glutethimide (500 mg/day), a drug known to cause enzyme induction (Corn, 1966). A tracer dose (1.5 gCi) of [14C]-aminopyrine was given orally in a fasting state. 14CO2, produced by hepatic demethylation of the drug, was collected by blowing into vials employing hyamine as a trapping agent. The vials were counted in a liquid scintillation counter and the specific activity of the 2 h breath sample was expressed as a percentage of the administered dose excreted in 2 h (ABT). The half life (Ti) of the decay of specific activity was calculated from at least four values obtained 2-6 h after administration of the drug. The following results were obtained:
ABT
(i) before glutethimide (ii) after glutethimide
Range (mean + s.d.) 7.5-12.6% (10.8 + 2.1) 9.4-13.2% (10.5 + 1.5)
T2 specific activity breath "4C02. (i) before glutethimide 106.9-137.8 min (126.6 + 11.6) (ii) after glutethimide 86.3-111.7 min (100.7* + 9.3) * P < 0.01 paired t-test. All five individuals demonstrated shortening of the Ti values following glutethimide treatment and in three cases studied there was also marked increase in urinary D-glucaric acid excretion. Thus there was clear evidence of induction of microsomal enzyme activity which was not reflected in a corresponding increase in the value for the ABT. We conclude that if the ["4C]-aminopyrine breath test is to be used as a screening test for drug induced microsomal induction, it is necessary to calculate the T, and not just simply take one sample at 2 h as has been previously suggested (Hepner & Vesell, 1976). References CORN, M. (1966). Effect of phenobarbital and glutethimide on biological half life of warfarin. Thromb. Diath. Haemorrh., 16, 606-612. GALIZZI, J., LONG, R.G., BILLING, B.H. & SHERLOCK, S.
(1978). Assessment of the [14C]-aminopyrine breath test in liver disease. Gut, 19, 40-45. HEPNER, G.W. & VESELL, E.S. (1976). Aminopyrine disposition: Studies on breath, saliva and urine of normal people and patients with liver disease. Clin. Pharmac. Ther., 20, 654-660. HEPNER, G.W., VESELL, E.S., LIPTON, A., HARVEY, H.A.,
WILKINSON, G.R. & SCHENKER, S. (1977). Disposition of aminopyrine, antipyrine, diazepam, and indocyanine green in patients with liver disease or on anticonvulsant drug therapy. Diazepam breath test and correlatives in drug elimination. J. lab. clin. Med., 90, 440-456.
