Gershon W. Hepner

Quantitative Assessment of Hepatic Function by Breath Analysis after Oral Administration of [14C]aminopyrine

The rate of hepatic metabolism of dimethylaminoantipyrine (aminopyrine), which occurs primarily through N-demethylation, was assessed by measurement of the specific activity of 14CO2 excreted in breath samples obtained 2 hours after oral administration of a trace dose of [14C]aminopyrine. The percentage of administered 14C excreted in 14CO2 in 2 hours was 7.0 +/- 1.3 (SD)% in control patients, and significantly less (P less than 0.01) in patients with portal cirrhosis (2.6 +/- 1.2%), fatty liver (4.7 +/- 1.1%), hepatitis (2.6 +/- 1.4%), and hepatic malignancy (3.5 +/- 1.8%). In 16 of 24 subjects with cholestasis not caused by malignant disease the mean 14CO2 excretion was normal. The 14CO2 excretion in patients with portal cirrhosis correlated highly with aminopyrine metabolic clearance rate (r equals 0.92), serum albumin (r equals 0.75), and retention of bromsulphalein (r equals 0.73). Abnormal 14CO2 excretion returned to normal in patients with hepatitis, when the hepatitis resolved. The data suggest that the aminopyrine breath test is a safe, simple, qualitative and quantitative liver function test.

Assessment of Aminopyrine Metabolism in Man by Breath Analysis after Oral Administration of 14C-Aminopyrine

Abstract To determine whether hepatic drug metabolism might be conveniently assessed by a breath analysis technic, 4-dimethyl-14C-amino-antipyrine (aminopyrine) was administered orally to healthy ambulant and nonambulant volunteers and to patients with portal cirrhosis; some of the volunteers were restudied after pretreatment with either phenobarbital or disulfiram. 14CO2 output was estimated semiquantitatively from interval breath samples. Aminopyrine metabolic clearance rate and 12-hour breath 14CO2 output in the healthy volunteers studied before and after drug pretreatment correlated highly(r = 0.91). The metabolic clearance rate was 46 ± 7 ml per minute (mean ± S.E.) in the patients with portal cirrhosis, and 122 ± 20 ml per minute in the healthy controls (p < 0.01). Twelve-hour breath 14CO2 output was 13.8 ± 1.5 per cent in the patients with portal cirrhosis, and 32.6 ± 2.3 per cent in the nonambulant controls (p < 0.01). The data suggest that in vivo breath analysis after administration of 14C-amino...

Abnormal vitamin D metabolism in patients with cirrhosis

To assess the role of hepatic function and alcohol on vitamin D metabolism, serum 25-hydroxyvitamin D (25-OHD) levels were measured in 20 healthy nonalcoholic control subjects, 31 “inactive” cirrhotics whose alcoholism was in remission, 8 alcoholic cirrhotics, and 15 alcoholics with normal liver function. Cirrhosis, but not alcoholism, was associated with low serum 25-OHD levels. The aminopyrine breath test (ABT) was performed because aminopyrine, like vitamin D3, is metabolized by hepatic microsomes; the ABT correlated highly (r-0.74,P<0.01) with serum 25-OHD in the inactive cirrhotics. After an intravenous injection of 120 μg vitamin D3, serum 25-OHD rose significantly within 24 hr in 6 healthy controls and 2 patients with celiac disease but not in 6 inactive cirrhotics. The data suggest impaired 25-hydroxylation of vitamin-D impaired in patients with cirrhosis, related predominantly to the degree of hepatic dysfunction.

Reduced drug elimination in congestive heart failure: Studies using aminopyrine as a model drug

Aminopyrine disposition was studied in 11 patients with congestive heart failure (CHF) and 15 control patients. The aminopyrine metabolic clearance rate was 29.7 +/- 7.1 ml/min (mean +/- SEM) in the patients with CHF and 125.1 +/- 5.7 ml/min (mean +/- SEM) in the control patients (p less than 0.01). The aminopyrine breath test was 2.6 +/- 0.4 per cent (mean +/- SEM) in the patients with CHF and 5.6 +/- 0.3 per cent (mean +/- SEM) in the control subjects (p less than 0.01). Probably due to fluid retention in CHF, the apparent volume of distribution of aminopyrine increased to 63.3 +/- 4.9 liters (mean +/- SEM) in patients with CHF from 43.1 +/- 1.9 liters (mean +/- SEM) in control patients, thereby further impairing aminopyrine elimination in patients with CHF (p less than 0.01). The aminopyrine breath test was measured in a group of eight patients before treatment for an acute episode of CHF and seven to 10 days after initiation of therapy: in each patient clinical improvement was associated with an increased aminopyrine breath test, mean values of aminopyrine breath test increasing from 2.8 per cent before treatment to 5.2 per cent after initiation of treatment (p less than 0.01). These results suggest that in patients with CHF hepatic drug-metabolizing activity is imparied, and the volume of distribution of drugs is increased, with consequent retardation in rates of drug elimination.

Aminopyrine disposition: Studies on breath, saliva, and urine of normal subjects and patients with liver disease

To investigate aminopyrine disposition, breath, saliva, and urine were collected from 25 control patients, 15 patients with hepatocellular disease, and 26 patients with hepatic neoplasm after oral administration of 2 µCi [14C]aminopyrine. The percentage 14C excreted in breath 14CO2 in 2 hr (aminopyrine breath test, ABT) correlated with the breath 14CO2 elimination rate (r = 0.92, p < 0.01), with the aminopyrine metabolic clearance rate (MCR) (r = 0.85, p < 0.01), and with the plasma half‐life of 4‐aminoantipyrine (r = −0.54, p < 0.05). The ABT permits study of aminopyrine disposition with simplicity, accuracy, and safety.

The Effect of Pelvic Irradiation on Ileal Function

Thirty-three patients with gynecological neoplasms undergoing radiotherapy to the pelvis had cholyl[1-14C]glycine breath tests to assess ileal function. Breath tests were performed on each patient in the first and fifth weeks of treatment and 19 of the patients had a third test three months post-treatment. In the first test, 29.9+/-16.8% (mean+/-SD) of the administered dose was excreted in breath 14C in 24 hours. This rose to 47.3+/-15.9% (t=6.08; p less than .001) in the fifth week and fell to 36.6+/-16% (t=2.29; p less than .05) at three months post-treatment. Eight patients had breath tests performed one year post-treatment and the test percentages were 32.7+/-7.8% (t=1.19; p less than .10). The increase in 14CO2 excretion in the fifth week of treatment occurred at a time when most patients were having diarrhea. The data suggest that bile acid malabsorption due to ileal dysfunction may be a factor in radiation-induced diarrhea which occurs in nearly all patients during pelvic irradiation.

The effect of pelvic irradiation on lactose absorption

Abstract Twenty-four patients undergoing pelvic irradiation for gynecologic malignancies had 14 C lactose breath tests performed in the first and fifth weeks of their treatment. The 14 C lactose breath test was performed by administering 2 μCi of 14 C lactose by mouth along with 50g of lactose. Breath samples were collected in ethanolic hyamine 1, 2 and 3 hr later; the radioactivity of the trapped 14 C0 2 was determined by liquid scintillation spectroscopy. In the first week of treatment the percentage of administered 14 C excreted as 14 C0 2 at 1, 2 and 3 hr was 1.7 ± 0.8% (mean ± SD), 4.5 ± 1.6% and 5.8 ± 1.4%, respectively. In the fifth week of treatment the 1-hr, 2-hr and 3-hr values were 1.2 ± 0.9%, 3.6 ± 2.0% and 4.7 ± 1.9%, respectively. The difference between the first week and fifth week test results at 1, 2, and 3 hr was statistically significant ( t = 2.64, p t = 2.24, p t = 2.95, p 14 C lactose breath test results in the fifth week and the stool frequency at that time ( r = −0.44, p 14 C lactose breath test results in the fifth week were below normal (

Decreased hepatic drug demethylation in patients receiving chemo-immunotherapy.

The effect of immunotherapy and chemotherapy on hepatic N‐demethylation of aminopyrine was studied by means of the aminopyrine breath test (ABT) in 32 patients with cancer. The aminopyrine breath test (ABT) was decreased in 3 of 11 patients (27.3%) receiving intradermal BCG (± DTIC) at a dose of 3 × 107 viable organisms. One of 4 (25%) patients receiving intradermal BCG (± DTIC) at 3 × 108 viable organisms per dose developed an altered ABT. Changes were not seen in patients receiving aerosol BCG (2 patients), intravenous C. parvum (2 patients), subcutaneous C. parvum (3 patients), and intravenous Cyclophosphamide (2 patients). Six of 7 patients (85.7%) receiving both intravenous C. parvum and Cyclophosphamide had a decreased ABT. These data indicate that chemo‐immunotherapy depressed hepatic aminopyrine N‐demethylation and suggests that patients treated with chemoimmunotherapy should be carefully observed for possible alterations of hepatic drug metabolism.

Dynamics of the enterohepatic circulation of the glycine conjugates of cholic, chenodeoxycholic, deoxycholic, and sulfolithocholic acid in man.

Highly sensitive and specific radioimmunoassays for cholylglycine, chenodeoxycholylglycine, deoxycholylglycine, and sulfolithocholylglycine have been used to study the kinetics of the enterohepatic circulation of these conjugated bile acids in 8 healthy subjects. Venous blood samples were collected over a 32-hr period, during which time the subjects ate three meals. Serum levels of cholylglycine and chenodeoxycholylglycine rose after each meal, and reached their maximum level within 30 to 60 min. A second chenodeoxycholylglycine peak occurred 2 to 3 hr after the first two meals in all subjects; a second peak was also found for cholylglycine in 3 of the 8 subjects. Serum deoxycholylglycine levels also rose postprandially; the peak level generally occurred 30 min later than that of cholylglycine. Serum sulfolithocholylglycine levels did not alter significantly after meals. The data indicate that the dynamics of the enterohepatic circulation of individual serum bile acids differ both quantitatively and qualitatively.

Investigation of a patient with Hodgkin's disease and cholestasis.

A patient with the cholestasis of Hodgkins disease was investigated. Our studies failed to relate the cholestasis to endocrine abnormalities. The patient had severely abnormal aminopyrine metabolism, suggesting more profound hepatocellular dysfunction than had previously been appreciated.