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The plasma disposition of three model substrates (lorazepam, indocyanine green, and antipyrine) and the formation clearance of antipyrine metabolites (3-hydroxymethylantipyrine, norantipyrine, and 4-hydroxyantipyrine) were evaluated in 15 subjects with mild cystic fibrosis and in 15 healthy control subjects. Plasma clearance was significantly greater in patients with cystic fibrosis for both lorazepam (1.7 +/- 0.4 versus 1.2 +/- 0.5 ml/min/kg) and indocyanine green (14.2 +/- 6.1 versus 9.1 +/- 3.0 ml/min/kg). In contrast, the clearance of antipyrine was not significantly different (1.0 +/- 0.7 versus 0.8 +/- 0.3 ml/min/kg), but the formation clearance for 3-hydroxymethylantipyrine was significantly greater in patients with cystic fibrosis. Lorazepam and antipyrine apparent steady-state volume of distribution were not different between groups. These results suggest that clearance of drugs that undergo conjugation (e.g., lorazepam) or biliary excretion (e.g., indocyanine green) is increased in patients with mild cystic fibrosis. In contrast, the increased formation clearance of only one antipyrine metabolite suggests that alterations in clearance of drugs metabolized by cytochrome P450 enzymes are substrate specific and isoform specific in patients with cystic fibrosis.

The effects of single and multiple oral doses of zileuton on the pharmacokinetics of antipyrine and indocyanine green were studied in 16 healthy, nonsmoking adult men by means of a double-blind, randomized, parallel placebo-controlled design. Indocyanine green disposition was not significantly altered by zileuton. Plasma antipyrine clearance declined by 20% (p < 0.0005) and 52% (p < 0.0005) after single and multiple dose zileuton exposure, respectively. Total urinary recovery of unchanged antipyrine and metabolites decreased with zileuton exposure. Selective declines from baseline of 16% (p = 0.007) and 20% (p = 0.003) after single-dose zileuton and 30% (p < 0.0005) and 43% (p < 0.0005) after multiple-dose zileuton were detected in recovery of 4-hydroxyantipyrine and 3-hydroxymethylantipyrine, respectively. Urinary recovery of the N-demethylantipyrine metabolite norantipyrine and percent of conjugation of 3-hydroxymethylantipyrine were unchanged by zileuton. In conclusion, zileuton therapy has no detectable effect on indocyanine green disposition but exerts marked effects on antipyrine plasma and urine metabolite disposition.

Effects of heme on hepatic xenobiotic drug metabolism were investigated in eight subjects with variegate porphyria. A single infusion of heme arginate (3 mg/kg heme) reversed rapidly the prolonged mean elimination half-life of antipyrine from 27.2 to 12.7 hours (p less than 0.001) and increased total clearance from 0.23 to 0.44 ml/min/kg (p less than 0.001). Excretion of 6 beta-hydroxycortisol and D-glucaric acid increased significantly during heme infusion. Excretion of urinary porphyrin precursors increased during the antipyrine test but was normalized by heme. It is concluded that in variegate porphyria a partial block in heme biosynthesis results in subnormal capacity of P450-associated monooxygenases, but this is easily normalized by exogenous heme.

Lorazepam, antipyrine, and indocyanine green were administered to 10 patients with severe head injuries as marker substrates of hepatic glucuronidation, oxidation, and hepatic blood flow, respectively. Pharmacokinetic parameter estimates were determined at baseline (20 to 80 hours after injury) and up to three additional times thereafter (study days 4, 7, and 14). Antipyrine clearance was increased significantly from baseline (0.50 +/- 0.31 ml/min/kg) on study days 4, 7, and 14 (p less than 0.0001). Increases in antipyrine clearance from baseline to the last study day were observed in all study patients ranging from 14% to 207%. A significant increase was also observed in lorazepam clearance on study day 14 relative to baseline (1.39 +/- 0.56 ml/min/kg) (p less than 0.005). Increases in lorazepam clearance occurred in seven of nine patients over time ranging from 9% to 130%. The unbound fraction of lorazepam did not change significantly over the study period. Likewise, no significant change was observed in the clearance of indocyanine green over time. Antipyrine clearance and alpha 1-acid glycoprotein (r = 0.41), and lorazepam clearance and C-reactive protein (r = -0.38) were significantly correlated (p less than 0.05). Similarly, antipyrine and lorazepam clearances were significantly correlated with injury severity based on the Acute Physiologic and Chronic Health Evaluation (APACHE II) score (r = -0.43 and r = -0.37, respectively). These findings suggest that hepatic oxidative and conjugative metabolism increase significantly over time in patients after acute head injury. An awareness of the potential for pharmacokinetic alterations in similarly metabolized drugs used for patients with severe head injuries is recommended.

Serum gamma-glutamyltransferase is used as a marker of hepatic enzyme induction. The kidney contains high activities of gamma-glutamyltransferase in the brush border membrane of the proximal tubule, from which it is released into urine. This study investigated the effect of phenobarbital and antipyrine, two inducers of hepatic monoxygenases and gamma-glutamyltransferase, on the urinary excretion of renal gamma-glutamyltransferase. Three groups (n = 6) of healthy male volunteers received 100 mg phenobarbital for 7 and 14 days and 1200 mg antipyrine for 7 days, respectively. Antipyrine and phenobarbital increased antipyrine elimination, serum gamma-glutamyltransferase, and the urinary excretion of renal gamma-glutamyltransferase, whereas urinary beta-N-acetylglucosaminidase, beta-glucuronidase, and total protein and glucose excretion were unchanged. No correlation was found between serum and urinary gamma-glutamyltransferase or both enzymes and antipyrine elimination. Increases in antipyrine elimination were positively correlated to increases in serum, but not urinary gamma-glutamyltransferase. The findings suggest that antipyrine and phenobarbital increase urinary gamma-glutamyltransferase excretion. However, the increase in urinary gamma-glutamyltransferase does not reflect the magnitude of hepatic enzyme induction.

Calcium antagonists have been shown to depress hepatic enzymes and accelerate hepatic blood flow. This study was designed to compare the effects of two calcium antagonists, isradipine and diltiazem, on antipyrine and indocyanine green (ICG) clearances in the elderly. Eighteen elderly subjects (aged 65 to 80 years) received either isradipine (5 mg every 12 hours), diltiazem (90 mg every 8 hours), or placebo (every 12 hours) for 4 days. On the third day after the study treatment, a 0.5 mg/kg dose of ICG was administered. Blood samples were obtained over 20 minutes for HPLC determination of ICG plasma concentrations. Ten minutes later, subjects ingested 1.2 gm antipyrine. Blood samples were obtained over 48 hours for HPLC determination of antipyrine plasma concentrations. Mean +/- SD antipyrine clearance after diltiazem (0.0258 +/- 0.0065 L/hr/kg) was significantly lower than that observed after isradipine (0.0334 +/- 0.0098 L/hr/kg) or placebo (0.0329 +/- 0.0082 L/hr/kg). Antipyrine clearance after isradipine was not significantly different from that after placebo. Mean +/- SD ICG clearances after diltiazem (9.17 +/- 1.35 ml/min/kg) or isradipine (9.57 +/- 1.82 ml/min/kg) were significantly higher than that observed after placebo (8.06 +/- 1.45 ml/min/kg). These findings suggest that diltiazem, but not isradipine, affects hepatic enzyme activity in the elderly. Both agents accelerate ICG clearance, a marker of hepatic blood flow.

Three patients with complete bile duct obstructions requiring a percutaneous biliary fistuala were given an oral dose of antipyrine. Drug elimination was assessed through plasma t1/2 studies and urine and bile excretion of both antipyrine and its metabolites. Urine metabolite patterns were in agreement with reference standards, but analysis of bile revealed no antipyrine metabolites and minimal parent compound (mean of total administered dose excreted from the bile fistulas was 4%). This finding was not predicted from previous experiments in the bile-cannulated rat and suggests caution regarding interspecies extrapolation of data concerning the hepatic disposition of certain commonly used test drugs in clinical pharmacologic studies.

The urinary excretion of D-glucaric acid and the plasma clearance of antipyrine were estimated during the acute phase of viral hepatitis and again during recovery. The plasma clearance of antipyrine was impaired during the acute stage of hepatitis, while the urinary excretion of D-glucaric acid was paradoxically high. Both parameters returned to normal during recovery. These findings suggest that the use of urinary D-glucaric acid excretion as an index of microsomal enzyme induction is unreliable when there is liver injury.

Effects of fasting on the metabolsim and distribution of antipyrine and tolbutamide were studied in 13 obese, but otherwise healthy, volunteers. Only 6 of the 13 subjects decreased their metabolic clearance rate (MCR) during fasting; no significant change occurred during fasting in the mean MCR of either drug. These results are in contrast with reported changed rates of drug metabolism in fasting experimental animals. The apparent volume of distribution (aVd) of antipyrine decreased during fasting in each of 7 subjects receiving oral test doses of antipyrine; the mean control value plus or minus standard deviation was 61 plus or minus 16 1, whereas during fasting the mean became 52 plus or minus 17 1. The aVd plus or minus SD of tolbutamide decreased in 4 of the 6 volunteers receiving intravenous test doses of tolbutamide; the mean control value in these6 volunteers was 8.3 plus or minus 1.7 1; during fasting it was 7.4 plus or minus 1.91.

Six normal male volunteers ingested a dose of 400 mg free testosterone daily as tablets over 21 days. By the end of treatment intravenous antipyrine half-life had decreased significantly from 8.0 +/- 2.7 to 5.7 +/- 2.6 hr. The subjects eliminated testosterone from serum more rapidly on the twenty-first day of testosterone ingestion than on the first day. Serum albumin, bilirubin, prothrombin, alanine-amino-transferase, and alkaline phosphatases were unchanged during the experiment. It is concluded that oral testosterone treatment induces the hepatic drug-metabolizing system including that of testosterone.

Large interindividual differences occur in the in vivo metabolism of drugs due to genetic and environmental factors. Our studies show that intraindividual variabilities in rates of metabolism are relatively low for antipyrine and phenylbutazone, which are drugs that are primarily metabolized by the liver and have low hepatic extractions; whereas in the case of phenacetin, a drug that undergoes extensive metabolism in the gastrointestinal tract or during its first pass through the liver, or both, intraindividual variations in plasma half-lifes and areas under the plasma concentration-time curves are of much greater magnitude. In our studies, no effort was made to control the lifestyles of our subjects. The variations in rates of drug metabolism did not result from assay procedures, since there was little variation in measured concentrations when the drugs were added to plasma and assayed on multiple occasions. Intraindividual variation occurring in subjects given the drug on 5 different occasions may be due to changes in the external environment or changes in internal physiologic parameters or both. Our studies confirm the usefulness of antipyrine as a test drug in studying drug metabolism in man and also demonstrate that the antipyrine test may be able to detect those subjects whose environments are perturbed by unidentified factors.

Antipyrine clearance (Cl(AP)) is widely used for assessment of microsomal liver function. The usual procedure involves collection of 4 to 7 samples of plasma or saliva obtained during 24 to 48 hr. To determine whether this procedure could be simplified it was compared with one based on a single sample (sCl(AP)) and an estimated volume of distribution (V(D)) in 142 persons. VD was estimated from body weight, in kilograms (BW), height, in centimeters (BH), age in years, and sex, or assumed to be 40 l. The agreement between values of Cl(AP and sCl(AP) increased with the time of the single sample and the two clearance estimates were nearly identical in all cases when the sample was taken after 18 hr. The method used for assessment of V(D) had only a small influence on the agreement. It is suggested that antipyrine clearance (in ml/min) is estimated as (formula: see text) where D is the dose of antipyrine (in mg), c(t) the concentration of antipyrine (in mg/t) at sampling time t (in min), t should be about 1440 min (24hr), and V(D) (in l) is calculated as 0.2363 X BW + 0.1962 X BH - 0.0272 X age - 10.26 (women) or 0.3625 X BW + 0.2239 X BH - 0.1387 X age - 14.47 (men). Little information is lost, however, if a fixed volume of 40 l is used. Then, if the dose is l gm, c(t) is expressed in milligrams per liter, and the sampling time is 24 hr, sCl(AP) = (3.28 - ln c(t)) X 28 ml/min.

The effects of chronic steroid contraceptive therapy on drug clearance from plasma were studied by using plasma antipyrine, phenylbutazone, and cholecalciferol half-lives in women. After 3 mo of oral steroid therapy (Norinyl, 2 mg; norethindrone + mestranol), the antipyrine half-life was increased in 3 of 6 subjects, phenylbutazone half-life was not consistently altered, and vitamin D3 half-life was increased in 3 of 4 patients. After 1 to 7 yr of oral steroid theraphy, the antipyrine half-life was longer while taking the contraceptive than when the contraceptive treatment was discontinued in 4 of 6 subjects, whereas that of phenylbutazone was not consistently altered.

The concentration of cytochrome P-450 and activities of the microsomal enzymes aryl hydrocarbon hydroxylase and ethylmorphine demethylase were measured in hepatic tissue obtained at biopsy from 69 patients. Antipyrine half-life (AP t1/2) was measured simultaneously as an in vivo marker of drug metabolism. Values for each index of the drug-metabolizing system varied greatly, but the mean values in groups of patients with mild hepatitis or inactive cirrhosis did not differ significantly from those of controls. Hepatic cytochrome P-450 content and aryl hydrocarbon hydroxylase activity were lower in patients with severe hepatitis or active cirrhosis than in controls, but ethylmorphine demethylase activity was unchanged in the patients. Drug ingestion was associated with enhancement of drug-metabolizing enzymes in all patients but those with severe liver disease; ethylmorphine demethylase activity was enhanced proportionately more than aryl hydrocarbon hydroxylase activity or cytochrome P-450 concentration. The observation that aryl hydrocarbon hydroxylase and ethylmorphine demethylase activities are influenced to a different extent by liver disease and also by drug ingestion indicates functional heterogeneity of the hepatic microsomal drug-metabolizing system in man. Correlations between t1/2 and hepatic drug oxidases were weak, even when allowance was made for variation in liver size. Thus, the rate of drug metabolism in vivo assessed by measuring AP t1/2 does not appear to be closely related to the activity of some hepatic drug-metabolizing enzymes.

Single-dose kinetics of 0.1 mg/kg intravenous diazepam, 10 mg/kg oral antipyrine, and 300 mg oral phenytoin were followed in healthy subjects before and after 400 mg metronidazole twice a day for 5 days. When data before metronidazole dosing were compared with those after metronidazole dosing, there were no changes in total plasma clearance of diazepam (0.53 and 0.65 ml/min/kg), antipyrine (39.0 and 38.0 ml/min/kg), or phenytoin (0.56 and 0.55 ml/min/kg). Plasma t 1/2s and volumes of distribution of the three drugs tested were not affected by metronidazole, but urinary excretion of 4-hydroxyantipyrine decreased after metronidazole dosing. There was no change in the elimination of phenytoin as its hydroxylated metabolite after metronidazole. It is concluded that, at therapeutic concentrations, metronidazole does not significantly inhibit oxidative drug metabolism.

A strong correlation was found in a carefully selected homogenous population (n = 57) between antipyrine plasma half-life and the percent induction of aryl hydrocarbon hydroxylase by 3-methylcholanthrene in mitogen-stimulated lymphocytes from the same individual. The correlation coefficient of r = 0.923 indicates that antipyrine and benzo[a]pyrene share one or several common determinants that are responsible for the observed interindividual variation in the oxidation rates of the two compounds. When a heterogenous population (n = 80) was studied, the above correlation was not found (r = 0.425).

A simple and senstitive radioimmunoassay has been developed for the determination of antipyrine levels in plasma and saliva of man. Antiserum to antipyrine was obtained from rabbits immunized with an immunogen prepared by covalently coupling N-(4-antipyrinyl)-succinamic acid to bovine serum albumin (BSA). The radioimmunoassay can detect antipyrine levels as low as 10 ng/ml of plasma or saliva, using a 0.1-ml sample. This contrasts with the sensitivity of a commonly used spectrophotometric method that can measure about 4,000 ng/ml using a 2-ml plasma sample. Agreement between the radioimmunoassay and spectrophotometric assay of antipyrine was excellent for plasma (r = 0.98) and salvia (r =0.97) when samples were analyzed from 6 subjects receiving 18 mg/kg of antipyrine. The correlation between plasma and saliva antipyrine half-lives using the radioimmunoassay and an 18 mg/kg dose of antipyrine was r = 0.90 (p less than 0.005). After a dose of 1.8 mg/kg of antipyrine, the drug disappeared monoexponentially from plasma and saliva for at least 51 hr, and the correlation between plasma half-life and saliva half-life was r = 0.97 (p less than 0.001) in the 6 subjects. Excellent agreement was also observed between half-lives after the high and low doses of antipyrine (r = 0.99, p less than 0.001 for plasma and r = 0.98, p less than 0.001 for saliva).

This study was undertaken to examine the influence of changes in dietary carbohydrate and protein content on the oxidation of antipyrine and theophylline in man. When the diets of 6 normal volunteers were changed from their usual home diets to low carbohydrate-high protein diets, the plasma half-life of antipyrine decreased from 16.2 hr to 9.5 hr, and the half-life of theophylline decreased from 8.1 hr to 5.2 hr. When the subjects' diets were changed from low carbohydrate-high protein diets to a high carbohydrate-low protein diets, the mean antipyrine half-life increased from 9.5 hr to 15.6 hr and the mean theophylline half-life increased from 5.2 hr to 7.6 hr. These changes in half-lives were accompanied by changes in metabolic clearance rates but not in the apparent volumes of distribution of the drugs tested. Qualitatively similar results were obtained when the subjects were placed on standard diets followed by the standard diets supplemented with carbohydrate or protein. Supplementing the standard diets with carbohydrate caused an increase in drug half-lives, whereas a protein supplement caused a decrease in the drug half-lives. These data demonstrate marked influences of nutritional factors on oxidative biotransformation of drugs in man.

In normal volunteers, chronic quinine administration shortened plasma antipyrine half-life and significantly increased the intraindividual correlation between the disposition of quinine and antipyrine. Decreased plasma antipyrine half-life appears to be due to a quinine-induced enhancement of antipyrine metabolism. A dose-dependent prolongation of plasma quinine half-life was observed and attributed primarily to an increased apparent volume of distribution of quinine, although our data did not permit separation of an effect on quinine metabolism from an effect on quinine distribution between the peripheral and central compartments. Plasma protein binding of quinine was similar at both the low and high doses of quinine. Studies in dogs given quinine intravenously revealed a biphasic plasma decay curve compatible with a 2-compartment open model for quinine disposition. Dose dependence of plasma quinine half-life in the dog after intravenous quinine eliminated altered gastrointestinal absorption of quinine as a cause for the dose dependence of plasma quinine half-life. These studies illustrate the importance of such conditions as dose and time of administration in determining the type and magnitude of interaction observed between drugs.

The plasma half-life and metabolic clearance rate of antipyrine, a drug metabolized by hepatic microsomal enzymes, were determined in 33 normal volunteers during a basal state and during fever induced with a single intramuscular injection of etiocholanolone. Of the 14 normal volunteers who achieved significant fever (fever index greater than 50), in 11 plasma antipyrine half-life was prolonged after a single oral dose of 10 mg/kg and antipyrine metabolic clearance rate was decreased. There was no significant change of these mean values in 19 normal volunteers who failed to develop significant fever (fever index smaller than 50). Therefore, under the conditions of this study plasma antipyrine half-life was prolonged, probably due to impaired hepatic metabolism, during etiocholanolone-induced fever, although no correlation was observed between the magnitude of fever and the extent to which plasma antipyrine half-life was prolonged. Failure to obtain such a correlation may be attributable to the very small range of temperature elevation, extending from 37.9 degrees C to 39.2 degrees C, in the group of 14 subjects achieving significant etiocholanolone-induced fever (fever index greater than 50). A higher dose of antipyrine (18 mg/kg) suppressed induction of fever by etiocholanolone; antipyrine is the only orally administered drug thus far shown to be effective in repressing etiocholanolone-induced fever.

Drug-metabolizing capacities were determined in 10 normal adults and 10 children in the age range from 1 to 8 years. Among the latter, 2 were normal and 8 had biochemical evidence of lead poisoning but no clinical expression of plumbism. There were no differences between the 2 normal children and the 8 lead-poisoned children in their capacities to metabolize two test drugs, antipyrine and phenylbutazone. The mean antipyrine half-life in the whole group of 10 children, 6.63 hr, was significantly lower than the mean half-life of 13.58 obtained in adults. The mean phenylbutazone half-lives in the children and adults, 1.68 and 3.16 days, respectively, also differed significantly. Thus children in the age range studied appear to metabolize drugs at almost twice the rate of adults which differs from findings in animals in which drug-metabolizing capacities increase with maturation. In two other children who showed clinical as well as biochemical manifestations of acute plumbism, antipyrine half-lives were signficantly longer than normal and therapy with EDTA led to restitution toward normal.

The effect of low-dose oral contraceptive steroids (OCS) on the kinetics of intravenous antipyrine was determined. Eight women (age, 23.1 +/- 1.1 yr (mean +/- SE); weight, 57.8 +/- 2.2 kg) using low-dose (less than or equal to 50 micrograms) estrogen oral contraceptive steroids (OCS) on a long-term basis were age- and weight-matched with eight controls (age, 23.4 +/- 0.8 yr; weight, 58.4 +/- 2.1 kg) not using OCS. All were nonsmokers taking no other drugs. OCS subjects had a longer antipyrine elimination half-life (t1/2 beta) than the controls (17.3 +/- 1.6 and 10.5 +/- 0.8 hr; p less than 0.005). Volume of distribution was similar for both groups (0.59 +/- 0.02 l/kg [OCS] and 0.58 +/- 0.02 l/kg). Total metabolic clearance of antipyrine was slowed in OCS subjects (0.41 +/- 0.03 and 0.66 +/- 0.05 ml/min/kg; p less than 0.001). Since volume of distribution and body weight are of the same order in both groups, prolongation of antipyrine t1/2 beta is the result of decreased total metabolic clearance. Thus, even low-dose estrogen containing OCS may impair clearance of other drugs.

In normal, nonmedicated volunteers and in patients with thyroid disorders the plasma half-lives of antipyrine, propylthiouracil, and methimazole were determined after single oral doses. The plasma half-liver plus or minus S.D. of antipyrine, propylthiouracil, and methimazole were 11.9 plus or minus 1.4 hr, 6.7 plus or minus 1.0 hr, and 9.3 plus or minus 1.4 hr, respectively, in normal volunteers, but were shortened to 7.7 plus or minus 1.2 hr, 4.3 plus or minus 0.7 hr, and 6.9 plus or minus 0.6 hr, respectively, in hyperthyroid patients. In hypothyroid patients the plasma half-lives of these drugs were prolonged to 26.4 plus or minus 4.0 hr, 24.7 plus or minus 34.5 hr, and 13.6 plus or minus 4.8 hr, respectively. Return to the euthyroid state restored plasma half-lives to or toward normal. Alterations in plasma drug half-lives during thyroid dysfunction appear to result mainly from accelerated hepatic microsomal drug metabolism in hyperthyroidism and retarded drug biotransformation during hypothyroidism.

Blood clearance of antipyrine, indocyanine green, and galactose were measured to evaluate the alterations of effective hepatic blood flow and hepatic intrinsic clearances in chronic liver diseases. Galactose blood clearance, which may be taken as effective hepatic blood flow, decreased by approximately 30% in patients with cirrhosis (12.49 +/- 0.76 ml/min/kg; mean +/- SE; n = 17) compared with normal subjects (18.17 +/- 1.03 ml/min/kg; n = 5). In patients with cirrhosis, intrinsic clearances of antipyrine (0.178 +/- 0.014 ml/min/kg; n = 17) and indocyanine green (6.19 +/- 1.38 ml/min/kg; n = 7) showed 61% and 85% reduction, respectively, compared with those of normal subjects (0.462 +/- 0.048 ml/min/kg; n = 5; 41.72 +/- 7.75 ml/min/kg; n = 5). Considering that indocyanine green and antipyrine are eliminated by different hepatic mechanism, these mechanisms may not be equally sensitive to decrements in hepatic function. In addition, fractional reductions of intrinsic clearances for these compounds are thus much greater than that of effective hepatic blood flow.

The influence of aminoglutethimide (AG) on antipyrine, theophylline, and digitoxin kinetics was examined. Antipyrine was given as a single test dose before and after 3 mo of AG treatment, whereas theophylline and digitoxin kinetics were investigated at steady state in patients receiving these drugs therapeutically before and after AG therapy. During AG treatment, mean clearance rates for antipyrine, theophylline, and digitoxin increased by 81%, 32%, and 109%. Together with earlier reports of effects of AG on warfarin and dexamethasone disposition and on its own metabolism, these findings indicate that AG is a potent inducer of drug metabolizing microsomal monooxygenases of the liver. Since many drugs known to be metabolized by this enzyme system are frequently used for concomitant conditions in patients with breast cancer, interactions with AG are to be expected.

Hospital patients with depressed arterial oxygen tensions (PaO2) from pulmonary disease were given antipyrine orally or intravenously. The half-time (t1/2) of disappearance from plasma was measured. Other patients with normal PaO2 measurements were treated similarly. Patients whose PaO2 was 55 or below had longer t1/2 times than those of patients with a PaO2 above 55. This observation parallels that made previously in rats.

Cimetidine has been shown to impair elimination of a number of drugs metabolized by the hepatic mixed-function oxidase enzymes. It is uncertain whether this is related to its histamine H2-receptor antagonism or to its intrinsic structure. Ranitidine is a more potent H2-receptor antagonist and has a completely different structure. Cimetidine (1 gm/day for 7 days) induced a 23% and 35% fall in mean systemic clearance of antipyrine and theophylline, whereas ranitidine (300 mg/day 7 days) had no significant effect on the clearance of either drug. Our data suggest that the inhibition of drug metabolism by cimetidine is not related to histamine H2-receptor antagonism.

The salivary half-life of antipyrine was used as a convenient procedure for estimating the relative rates of drug metabolism in man. The concentration ratio of antipyrine in plasma and saliva was one over a 24-hr period following the oral or parenteral administration of the drug to man and rat. Phenobarbital, a known stimulator of drug metabolism in animals and man, increased markedly the elimination of antipyrine from saliva of rats, while SKF-525A, a potent inhibitor of drug metabolism, prolonged the elimination of antipyrine from rat saliva. In addition, the known sex difference in the metabolism of drugs in the rat was detected by measuring the elimination rate of antipyrine from saliva of male and female rats. The clinical application of the procedure indicated that a group of epileptic patients treated with anticonvulsants for more than 2 mo had a mean antipyrine salivary half-life of 4 hr, whereas a mean half-life of 13 hr was found in a group of normal volunteers. The results show that the elimination rate of antipyrine from saliva is a useful index of drug metabolism in animals and man.

The mean plasma half-life (T1/2) of antipyrine was prolonged (21.69 +/- 1.92 hr) in a group of 10 patients with hereditary hepatic porphyria, 8 of whom had acute intermittent porphyria (AIP) confirmed by decreased erythrocyte uroporphyrinogen-1-synthetase (URO-S) activities and 2 of whom had mixed hepatic porphyria, in comparison to the mean of 20 normal control subjects (12.65 +/- 0.86 hr, p less than 0.01). Antipyrine T1/2 was especially prolonged in patients with a history of more severe symptoms, but there was no correlation with the degree of elevation in urinary excretion of the porphyrin precursors delta-aminolevulinic acid (ALA) and porphobilinogen (PBG). In 7 completely latent carriers of the AIP gene defect who had normal urinary ALA and PBG levels, the elimination rates of antipyrine from plasma were entirely normal. Phenylbutazone T1/2s were normal in 10 porphyric patients tested. These results demonstrate that the cytochrome P-450-dependent enzyme system for oxidizing antipyrine, but not that for phenylbutazone, is impaired in some AIP individuals in whom the gene defect for the disorder is clinically expressed and that this impairment may be related to the severity of the disease. The partial decrease in URO-S activity characteristic of AIP does not result in a profound or generalized decrease in hepatic cytochrome P-450 function, however, even when there is sufficient derangement in the hepatic heme biosynthetic pathway to lead to excessive excretion of chemical intermediates in the pathway.