Plasma Clearance Of Antipyrine Research Articles

Plasma Concentration-Response Relationship for Cimetidine Inhibition of Drug Metabolism in the Rat

Cimetidine inhibition of antipyrine elimination has been studied in the rat over a range of steady state cimetidine concentrations. Cimetidine is a potent inhibitor of antipyrine metabolism with a concentration of about 1.25 mg/liter causing a 50% decrease in the total plasma clearance of antipyrine. The degree of inhibition of antipyrine clearance caused by cimetidine is dependent upon its plasma concentration, but the relationship is not linear. The formation clearances of all antipyrine metabolites measured--3-hydroxymethylantipyrine, 4-hydroxyantipyrine, and norantipyrine--are inhibited by cimetidine at all concentrations used. The susceptibility of the different metabolites to cimetidine inhibition does vary. The renal clearance of antipyrine was also decreased by cimetidine by an unknown mechanism. Analysis of the individual formation clearances suggests that the inhibition of oxidative metabolism due to cimetidine is caused by its binding to two classes of enzyme sites--a high affinity, low capacity and a low affinity, high capacity site. These two different sites would appear to be responsible for the production of different metabolites of antipyrine. The true nature of the selectivity of cimetidine inhibition of antipyrine metabolism is apparent from the formation clearances but not from the urinary metabolite patterns.

The impact of acute phase response on the plasma clearance of antipyrine, theophylline, phenytoin and nifedipine in rabbits.

The impact of acute phase response (APR) on the plasma clearances of antipyrine, theophylline, phenytoin and nifedipine was studied using 50 female rabbits. APR was induced by a bolus intramuscular injection of Escherichia coli lipopolysaccharide (LPS, 50 microg/kg). No abnormal findings, other than an increase in rectal body temperature and the plasma concentration of interleukin-6 (IL-6), were observed in the LPS-treated animals. Twenty-four hours after LPS injection, the pharmacokinetic parameters of the four drugs were obtained following intravenous administrations of antipyrine (7 mg/kg), theophylline (5 mg/kg), phenytoin (10 mg/kg) and nifedipine (1 mg/kg). Total body clearances of antipyrine, theophylline, phenytoin and nifedipine in LPS-treated rabbits decreased, and terminal elimination half-life and the mean residence time of these drugs increased compared with those in the control rabbits. The apparent volume of distribution for phenytoin and nifedipine increased after the LPS injection, although the binding percentage of the drugs with plasma protein did not change. These results suggested that APR appears to decrease the plasma clearances of these drugs in rabbits, which may be due to the suppression of the activity of cytochrome P450 enzymes.

The effect of sex on antipyrine metabolism in cattle at different ages.

The aim of this study was to determine the effect of sex on the metabolism of antipyrine by measuring the antipyrine plasma clearance as well as excretion of three major metabolites in urine in cattle of different ages. The experiment was carried out on 10 female and 10 male cattle of Black and White breed. The antipyrine test was carried out at 1, 2, 4, 6, 8, 12 and 18 months of age for each animal (single dose of 10 mg/kg antipyrine were given intravenously). The concentrations of antipyrine, 4-hydroxyantipyrine (4-OHA), 3-hydroxymethylantipyrine (HMA) and norantipyrine (NORA) were measured in plasma and urine by high performance liquid chromatography (HPLC). The apparent volume of distribution of antipyrine (aVd) decreased significantly between 1 and 18 months of age, but mean aVd values observed in males and females were not statistically different. The experimental period was characterised by a steady decrease (statistically significant) in antipyrine half-life (t1/2beta). These values did not differ significantly between males and females under 12 months. In 12 and 18 month-old animals the antipyrine half-life in the females was significantly shorter than in the males. The systemic clearance (Cls) of antipyrine increased significantly between 1 and 18 months of age. No significant differences were observed between systemic clearance of antipyrine in males and females under 12 months. In 12 and 18 month-old animals the Cls values were significantly higher in females than in males. Following intravenous administration, recovery of antipyrine and its three main metabolites increased significantly with age. These values did not differ significantly between males and females under 12 month of age. In 12 and 18 month-old females the excretion of 4-OHA and HMA in urine was significantly higher than in males at the same age. The excretion of NORA and unchanged antipyrine in males and females did not differ significantly. The partial clearances of antipyrine metabolites (Cl(m)) increased significantly between 1 and 18 months of age. No significant differences were observed between Cl(m) values in males and females under 12 months of age. In 12 and 18 month-old females the partial clearances of 4-OHA and HMA were significantly higher than in males. The clearance of NORA was significantly higher in 18 month-old females than in males. In conclusion, we report a sex-linked difference in plasma antipyrine clearance and urinary excretion of the main metabolites of antipyrine in cattle over 12 months of age, the females being the more active metabolizers.

Exercise-training-induced alterations in hepatic function in mares.

The effects of exercise training on hepatic function in horses were determined by studying the plasma clearance of antipyrine (20 mg/kg iv) in adult mares that either underwent treadmill training for 5 wk (n = 7) or remained in box stalls for the same time period (n = 6). Training consisted of treadmill exercise at 60% (12 min/day) and 90% (3 min/day) of pretraining maximal oxygen consumption (V(O2)max) for 6 days/wk for 5 wk. V(O2)max and velocity to obtain a blood lactate concentration of 4 mmol/l were significantly increased (from 129 to 149 ml x min-1 x kg-1 and from 5.6 to 6.1 m/s, respectively) as a result of training. The plasma clearance and volume of distribution of antipyrine increased significantly in the trained group (from 5.5 to 6.4 ml x min-1 x kg-1 and from 813 to 881 ml/kg, respectively) and decreased significantly in the untrained group. Elimination half-lives did not change as a result of training or box rest. Increases in plasma antipyrine clearance were indicative of an increase in hepatic metabolism of antipyrine. Increases in the volume of distribution of antipyrine suggest that total body water increases as a result of exercise training.

Influence of short-term water deprivation on antipyrine disposition in calves

The effect of four days water deprivation on the metabolism of antipyrine was studied in female Holstein-Friesian calves, aged 24 to 25 days, by measuring the antipyrine plasma clearance and the excretion of three major metabolites of antipyrine in urine. Water deprivation was associated with a statistically significant (P≤0·01) increase in the plasma antipyrine elimination half-life from 10·85(1·14) hours to 14·00(1·05) hours. In water deprived calves the systemic clearance of antipyrine was significantly (P<0·05) decreased from 0·75(0·07) ml min −1 kg −l to 0·56(0·05) ml min −1 kg 1. The excretion of three major metabolites of antipyrine: 4-hydroxyantipyrine, 3-hydroxymethylantipyrine and norantipyrine in urine was significantly (P<0·01) decreased after water deprivation. In the control group no significant differences between the pharmacokinetic parameters of antipyrine in 24 to 25 and 28 to 29 day-old calves were observed. Also urinary profiles of antipyrine in calves from the control group did not differ significantly between 24 to 25 and 28 to 29 days of life. Our data indicate that water deprivation inhibits antipyrine elimination in calves.

Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions.

The effect of aging on drug metabolism in humans has not yet been completely described. Two hundred twenty-six patients with equal histopathologic conditions were investigated. The cytochrome P450 contents in the liver biopsy samples, the plasma antipyrine clearance rates after oral administration and, as an independent control of vitality, serum testosterone levels were determined. Cytochrome P450 content in subjects from 20 to 29 years of age was 7.2 +/- 2.6 nmol.gm-1, increased during the fourth decade (+7.2%, p = NS), declined after 40 years (-16%, p < 0.01) to a level that remained unaltered up to 69 years, and declined further after 70 years (-32%, p < 0.001). The antipyrine (phenazone) clearance rate in young subjects was 46.4 +/- 18.5 ml.min-1, remained unaltered during the fourth decade, and declined after 40 years by a rate of 0.34 ml.min-1 per year toward old age (-29%, p < 0.001). The half-life in young subjects was 9.5 +/- 2.0 hours and increased after 30 years toward old age (+26%, p < 0.001). The volume of antipyrine distribution, 0.46 +/- 0.12 L.kg-1 in young subjects, decreased after 30 years (-11%). In line with the testosterone content, the decrease in drug metabolism was equal in both sexes. This study shows a reduction of in vitro and in vivo drug metabolism with age in humans. The data suggest that at least three age groups--young, middle-aged, and elderly--should be included in the evaluation of the pharmacokinetics of a new drug. The reduction of drug metabolism (-30%) after 70 years of age indicates that care is needed in the prescription of drugs for elderly subjects.

Evaluation of hepatic function using 99mTc-galactosyl human serum albumin (GSA) scintigraphy: comparison with antipyrine plasma clearance

99mTc-galactosyl human serum albumin (GSA) is a new scintigraphy agent which binds specifically to asialoglycoprotein receptors on hepatocytes, and can be used to evaluate hepatic function. Indocyanine green (ICG) is hepatic blood flow-dependent, while antipyrine plasma clearance is independent of blood flow and thus antipyrine plasma clearance is an excellent parameter with which to assess liver function. In this study, we investigated the relationship between GSA examination and antipyrine plasma clearance to assess the usefulness of GSA in evaluating metabolic function of the liver. Studies were performed on 22 patients with liver diseases. Antipyrine plasma clearance measurement, ICG testing and biochemical analysis of blood were performed at the same time as GSA examination. GSA HH15 and antipyrine plasma clearance showed a good correlation ( r = −0.702, P < 0.0005). On the other hand, ICGR15 showed a poor correlation with antipyrine plasma clearance ( r = 0.449, P < 0.05). The results of this study suggest, that hepatic function determined using GSA is more closely related to the metabolic capacity of hepatocytes than to hepatic blood flow.

In vitro and in vivo oxidative biotransformation in the West-African dwarf goat (Caprus hircus aegagrus): substrate activities and effects of inducers.

1. Cytochrome P450 activities in vivo and in vitro and enzyme induction by phenobarbital, beta-naphthoflavone, isoniazid and triacetyloleandomycin were investigated in the female dwarf goat. In vivo kinetics of antipyrine, sulphadimidine and caffeine were studied separately and as a combination ("cocktail'). After establishing a lack of interaction between these compounds the effects of the inducing agents were investigated. In vitro, hepatic microsomal enzyme activities and apoprotein levels were determined. 2. In the beta-naphthoflavone treated goat, the microsomal ethoxy-resorufin-O-deethylation rate was markedly increased. beta-naphthoflavone also induced caffeine plasma clearance but did not affect microsomal caffeine 1- and 3-demethylation rates. After phenobarbital treatment, caffeine plasma clearance was also increased. In contrast with beta-naphthoflavone treatment, phenobarbital treatment resulted in an increase of microsomal caffeine 1- and 3-demethylation rates. 3. Goat liver microsomes were able to hydroxylate tolbutamide, predominantly a CYP2C9 activity in man, and debrisoquine, a CYP2D activity in different species. These activities were not affected by either beta-naphthoflavone or phenobarbital. Sulphaphenazole was found to be a more potent inhibitor of tolbutamide hydroxylation than sulphadimethoxine. Quinine was a more potent inhibitor of debrisoquine hydroxylation than was quinidine. 4. As expected, the microsomal aniline-4-hydroxylation rate (CYP2E) was increased after isoniazid treatment. 5. The microsomal testosterone 6 beta-hydroxylation rate (CYP3A) was increased after phenobarbital and triacetyloleandomycin treatment. Antipyrine plasma clearance was also increased after phenobarbital treatment. 6. As cytochrome P450 activities and inducibility in the dwarf goat show many resemblances to those in man, they may be of value as a model for human biotransformation research.

Assessment of antipyrine kinetics from saliva or plasma: influence of age

The purpose of this study was to investigate whether antipyrine estimation in saliva provides valid information on plasma antipyrine clearance (AP Cl) and can be useful as an index of changes in drug metabolism with age. Antipyrine kinetics was studied in 93 elderly (mean age 82 years) and 23 young (mean age 29 years) volunteers. Plasma antipyrine half-life ( APt 1 2 ) increased and plasma AP Cl declined with age. No significant difference between plasma- and saliva-derived parameters was found in either young or old subjects. However, the saliva/plasma AC Cl ratio tended to increase with age. A highly significant correlation between saliva and plasma AP Cl or APt 1 2 was found in young subjects. Values were less closely related in the elderly and the slope of the saliva/plasma AP Cl relationship was significantly different in both groups of subjects. Residual variance was higher in the regressions corresponding to the elderly. The findings in the study indicate that the relationship between saliva and plasma kinetics in young subjects becomes less reproducible with age.

Effects of Flumethrin on Hepatic Drug-Metabolizing Enzymes and Antipyrine Disposition in Rats

The effects of repeated exposure to the pyrethroid insecticide flumethrin (40 mg/kg intraperitoneally once a day for 6 days) on the activity of cytochrome P450-dependent monooxygenases and UDP-glucuronosyltransferase as well as on antipyrine disposition were investigated in male Wistar rats. Pretreatment with flumethrin decreased the activities of NADPH-cytochrome c reductase (38%), aniline hydroxylase (53%), aminopyrine N-demethylase (54%), and UDP-glucuronosyltransferase (34%), and the content of cytochrome P450 (36%) in hepatic microsomes. Total plasma clearance of antipyrine was decreased by flumethrin pretreatment (54%), while the elimination half-life at beta phase and the mean residence time of antipyrine were increased (96 and 88%, respectively). Urinary excretion of norantipyrine, 4-hydroxyantipyrine, and 3-hydroxymethylantipyrine was decreased by 60, 38, and 33%, respectively, in the 96 hr after flumethrin treatment. In addition, the rate constants for formation of each of these metabolites were decreased by an average of approximately 74%. These findings provide evidence that flumethrin exposure diminishes hepatic enzyme levels and catalytic activities of monooxygenase systems as well as oxidative metabolism of antipyrine.

Selective effects of a bacterial infection (Actinobacillus pleuropneumoniae) on the hepatic clearances of caffeine, antipyrine, paracetamol, and indocyanine green in the pig.

1. In order to investigate the effect of a bacterial acute phase response model on drug disposition in vivo, plasma clearances of antipyrine, caffeine, paracetamol and indocyanine green were investigated in the healthy and Actinobacillus pleuropneumoniae-infected pig. 2. Indocyanine green plasma and endogenous creatinine clearance were not changed during the infection, which indicates that hepatic blood flow and renal function were not significantly affected. 3. In the A. pleuropneumoniae-infected pig, plasma clearances of antipyrine and caffeine, both marker substrates for hepatic oxidative biotransformation, were decreased by 72 and 68% respectively. The clearance of paracetamol, a drug mainly glucuronidated in the pig, was reduced by 39%. 4. It is concluded that the most important change in drug elimination during an acute phase response induced by A. pleuropneumoniae is a suppression of oxidative hepatic biotransformation.

Dose-dependent pharmacokinetic interaction between antipyrine and paracetamol in vivo and in vitro when administered as a cocktail in pig.

1. The pharmacokinetic interactions between paracetamol (PA) and antipyrine (AP) were studied in pigs in order to investigate the usefulness of this combination for the simultaneous assessment of oxidative and conjugative metabolism. 2. When both drugs were given at a dose of 5 mg/kg, AP plasma clearance was reduced from 2.22 to 0.96 lh-1 kg-1. PA clearance was not changed in comparison with control values. 3. At a dose of 2 mg/kg no pharmacokinetic interaction between the two drugs was observed. 4. The only oxidative AP metabolite found in urine was 4-hydroxyantipyrine (4-OHA). It accounted for 80% of the dose and, like PA, it was completely glucuronidated. 5. The glucuronidation of PA has been studied in vitro in pig liver microsomes. The apparent Km value for PA glucuronidation was 40 mM with a Vmax = 54 nmol min-1 mg protein-1. To determine if 4-OHA and PA competed for the same UDP-glucuronosyl-transferase, the effect of 4-OHA and AP on PA glucuronidation was studied. It appeared that 4-OHA was a competitive inhibitor with a Ki app = 0.07 microM, whereas AP had no effect. 5. Results suggest a dose-dependent interaction between AP and PA, which may be due to competition at the level of glucuronidation. Therefore, the usefulness of AP and PA in vivo in a cocktail for metabolism studies is limited.

Effect of gonadal hormones on the plasma clearance and metabolite formation of antipyrine in the dwarf goat.

The effect of gonadal hormones on the plasma elimination and urinary metabolite profile of antipyrine was studied in dwarf goats. Female goats were treated with testosterone and male goats were treated with 17 beta-oestradiol. Castrated males were treated with either testosterone or 17 beta-oestradiol. Antipyrine (25 mg/kg, i.v.) was given both before and after the hormonal treatments. The effects of the hormonal status on the plasma elimination of the parent compound were not consistent. This was possibly due to the fact that formation of the main metabolite of antipyrine in the goat, 4-hydroxy antipyrine (OHA), was not affected by sex or hormonal treatment. On the other hand, there were clear effects of hormonal status on urinary excretion of the three other metabolites. In females and castrated males testosterone suppressed the formation of norantipyrine (NORA), 3-hydroxymethylantipyrine (HMA) and 4,4'-dihydroxyantipyrine (DOHA). Intact males produced smaller amounts of these metabolites than females. It is concluded that distinct xenobiotic metabolizing pathways exist in the dwarf goat, which are influenced in their activity by gonadal hormones. This confirms previous findings in rats and mice. The possibility that sex hormones influence drug metabolism in food-producing animals could have consequences for veterinary therapeutics and public health. This study also demonstrates that, when using the antipyrine test for the assessment of hepatic drug metabolism, it is very important to include the determination of metabolites.

Effect of early treatment with rafoxanide on antipyrine clearance in sheep infected with Fasciola hepatica.

1. The effect of the salicylanilide compound rafoxanide against immature stages of Fasciola hepatica was investigated in sheep using a series of antipyrine clearance tests and measuring glutamate dehydrogenase and gamma-glutamyl transferase activities in plasma. 2. Three animal groups were used. In two groups, sheep were infected with 200 metacercariae each. Four weeks after infection one of the two groups was treated with rafoxanide and the other was left untreated. The third group was unparasitized and also received rafoxanide. 3. Infection was confirmed by post-mortem examination of the livers of infected sheep. Infection did not alter the plasma disposition of rafoxanide. 4. The efficacy of rafoxanide, as assessed by the reduction in the number of adult flukes in treated animals compared with controls, was 85%. 5. Glutamate dehydrogenase activity fell dramatically 2 weeks after treatment but increased again at 12 weeks post-infection in the infected rafoxanide-treated group. 6. Antipyrine clearance decreased between 8 and 14 weeks post-infection in untreated sheep. In the infected rafoxanide-treated group plasma clearance of antipyrine remained unchanged until 10 weeks after rafoxanide administration when it decreased from the preinfection value of 5.09 to 3.90 ml.kg/min. Rafoxanide did not affect antipyrine disposition in uninfected sheep. 7. It was concluded that rafoxanide had an incomplete anthelmintic effect against immature stages of Fasciola hepatica, and that surviving parasites caused delayed liver damage which was reflected in an elevation in glutamate dehydrogenase activity and decreased plasma clearance of antipyrine.

Metabolism of antipyrine and sulphadimidine in dwarf goats: effects of the enzyme-inducing agents phenobarbital, troleandomycin and rifampicin.

1. Antipyrine (AP) and sulphadimidine (SDD) plasma elimination and metabolite formation were studied in dwarf goats before and after treatment with phenobarbital (PB), triacetyloleandomycin (TAO), and rifampicin (RIF). 2. PB treatment significantly increased AP plasma clearance in both male and female goats. With SDD, only male goats were studied, which showed a significant increase of SDD plasma clearance following PB treatment. 3. After PB treatment, partial clearance values of four AP metabolites, 3-hydroxymethylantipyrine (HMA), norantipyrine (NORA), 4-hydroxyantipyrine (OHA) and 4,4'-dihydroxyantipyrine (DOHA), were significantly increased. This induction effect was different for the individual metabolites and also showed sex-dependency. 4. In PB-induced male goats the formation of the hydroxylated SDD metabolites, 6-hydroxymethyl-SDD and 5-hydroxy-SDD, was significantly increased. 5. After TAO treatment, female goats showed a slightly reduced AP plasma clearance and a decreased partial clearance of two AP metabolites, HMA and DOHA. There was no effect on SDD plasma elimination or metabolite excretion. 6. In male goats, RIF had no effect on plasma elimination of AP and SDD. With SDD, it decreased the urinary excretion of the unchanged drug and its N4-acetylated metabolite. 7. Induction/inhibition studies of drug metabolism in food-producing animal species are desirable to gain more insight into the regulation of enzymes involved in the metabolism of xenobiotics.

Effect of deltamethrin on antipyrine pharmacokinetics and metabolism in rat

The effect of deltamethrin pretreatment on the pharmacokinetics and metabolism of antipyrine was studied in male rats. The total plasma clearance of antipyrine was significantly decreased by deltamethrin pretreatment (20 mg/kg and 40 mg/kg daily for 6 days prior to antipyrine administration), while the elimination half-life at beta phase, the area under the concentration-time curve and the mean residence time of antipyrine were significantly increased. The magnitude of the observed changes was dose dependent. The urinary excretion of norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine was decreased by 39%, 32% and 26%, respectively (p less than 0.001) in the presence of deltamethrin. In addition, the rate constants for formation of each of these metabolites were significantly decreased by an average of approximately 71%. These results suggest that deltamethrin is capable of inhibiting oxidative metabolism, a finding which could be of clinical and toxicological significance.

Species- and sex-related differences in the plasma clearance and metabolite formation of antipyrine. A comparative study in four animal species: Cattle, goat, rat and rabbit

1. The plasma disposition of antipyrine, and its urinary metabolite pattern, were studied in both sexes of four animal species: rat, dwarf goat, rabbit and cattle. 2. No sex differences in plasma elimination of antipyrine were found in rabbit and goat; however, in rat and cattle the effect of sex was marked. As expected, male rat showed a higher plasma clearance value than female. In contrast bulls showed a significantly lower clearance value than cows. 3. Metabolite patterns varied widely from one species to another. The major urinary metabolite in rabbit and the two ruminant species was 4-hydroxy-antipyrine (OHA), whereas in rat 3-hydroxymethylantipyrine (HMA) was quantitatively the most important metabolite. 4. HMA was excreted in the 24 h urine in larger amounts by male rats than by females. Metabolism of antipyrine to HMA was also sexually different in the dwarf goat, but in this species females were more active than males. The effect of sex on the metabolite pattern in cattle was marked. 5. It is concluded that in ruminants there may be xenobiotic metabolic pathways which are under hormonal control, just as there are in rats and mice. If hormones influence drug metabolism in food-producing animals, residue levels of xenobiotics or their metabolites in food from animal origin may differ with the sex of the animal, or may be altered after treatment with anabolic hormones.

Effect of ciprofloxacin on antipyrine pharmacokinetics and metabolism in rats

The effect of ciprofloxacin pretreatment on the pharmacokinetics and metabolism of antipyrine in male rats was studied. The animals received oral antipyrine (20 mg/kg of body weight) with and without ciprofloxacin pretreatment (40 mg/kg orally once a day for 8 days). The total plasma clearance of antipyrine was decreased from 0.130 +/- 0.007 to 0.090 +/- 0.005 liter/h (mean +/- standard error of the mean) (P less than 0.01) by ciprofloxacin, while the half-life at beta (elimination) phase and the area under the concentration-time curve for antipyrine were increased from 1.90 +/- 0.22 to 2.83 +/- 0.29 h (P less than 0.05) and from 43.25 +/- 3.35 to 52.41 +/- 2.31 mg.h/liter (P less than 0.05), respectively. The urinary excretions of norantipyrine, 4-hydroxyantipyrine, and 3-hydroxymethylantipyrine decreased by 73, 43, and 54%, respectively (P less than 0.001), in the 96 h after ciprofloxacin treatment. In addition, the rate constants for formation of each of these metabolites were significantly decreased, by an average of approximately 75%. These results suggest that ciprofloxacin is capable of inhibiting oxidative metabolism. This finding could be of clinical significance for drugs that are highly dependent of metabolic pathways, such as those inhibited in this study.

Hepatic drug metabolism is increased in poorly controlled insulin-dependent diabetes mellitus

In addition to increased glycosylation of hemoglobin, abnormalities of other heme proteins such as cytochrome P-450 might also occur in patients with insulin-dependent diabetes mellitus. Antipyrine is a useful marker drug for cytochrome P-450 dependent hepatic drug metabolism. Antipyrine kinetics and urinary excretion of antipyrine metabolites were measured in 14 patients with insulin-dependent diabetes mellitus in poor metabolic control. Improvement in diabetic control in 9 patients, as measured by more normal HbA1 values, led to normalization of plasma antipyrine half-time (t1/2) and metabolism: the mean antipyrine t1/2 slowed from 4.7 +/- 0.2 (SEM) initially to 7.8 +/- 0.3 h in these 9 patients and was thus nearly identical to that of normal subjects 8.6 +/- 1.0. Antipyrine plasma clearance improved in the 9 diabetic patients whose diabetic control improved. The apparent volume of distribution was normal on both occasions in the diabetic patients. These findings provide a new argument for tight metabolic control in patients with insulin-dependent diabetes mellitus.

Influence of vitamin E supplementation on antipyring clearance in the cebus monkey

Clearance of antipyrine was assesed to evaluate the effect of dietary vitamin E supplementation on the drug-metabolizing enzyme system in young (4–6 yrs) and older (15–20 yrs) Cebus monkeys (Cebus albifrons). The monkeys were supplemented with 75 IU vitamin E for 43 days. Plasma vitamin E and plasma antipyrine clearance and elimination half-life were measured before and after supplementation. Vitamin E supplementation increased plasma vitamin E in both age groups. In the young animals, vitamin E supplementation significantly (p<0.05) increased antipyrine clearance. The effect of dietary vitamin E on the decreased half-life and increased clearance of antipyrine became more significant when both age groups were combined. These findings are consistent with the concept that dietary antioxidants enhance clearance of drugs undergoing hepatic oxidative metabolism.