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PubMed1987

Inhibition and induction of metronidazole and antipyrine metabolism.

The effect of cimetidine, antipyrine and phenobarbitone on the pharmacokinetics of intravenous metronidazole and oral antipyrine has been examined in 7 healthy volunteers. The administration of cimetidine for 24 h before and throughout the sampling period failed to alter the total clearance of metronidazole or the rate of formation of the hydroxy metabolite, whereas the total and partial clearances of antipyrine were decreased 0.74 and 0.6-0.7-fold, respectively. Seven days of phenobarbitone or antipyrine administration increased the total clearance of metronidazole 1.51- and 1.86-fold, respectively, and the total antipyrine clearance was 1.22 or 1.46-fold increased, respectively. The rate of metronidazole hydroxylation was significantly enhanced by both enzyme inducers. The partial clearance of antipyrine to the normetabolite was significantly increased by both inducers, whereas the rate of 4-hydroxylation was significantly increased only by prior antipyrine administration. The results indicate that the hydroxylation of metronidazole is not inhibited by cimetidine, but that it is inducible by phenobarbitone or antipyrine. It is suggested that metronidazole and antipyrine are metabolized by different enzymatic pathways.

Adult↗
PubMed1986

Effect of fetal and maternal intravascular antipyrine infusion on maternal plasma prostaglandin concentrations in the pregnant sheep at 104 to 127 days' gestation.

Antipyrine is commonly used to measure umbilical and uterine blood flow in the pregnant sheep. In the present experiment we investigated the effect of antipyrine on prostaglandin metabolism. Four pregnant ewes at 104 to 127 days' gestation were infused with either 1, 4, or 15 mg of antipyrine per minute via the fetal jugular vein. The 15 mg X min-1 dose was also infused into the maternal jugular vein in a fourth experiment. Prostaglandins in the uterine vein draining the pregnant horn were measured by radioimmunoassay and antipyrine by high-performance liquid chromatography. No change in the concentrations of either 13,14-dihydro-15-keto-prostaglandin F2 alpha or 6-keto-prostaglandin F1 alpha was observed with infusion of antipyrine at 1 mg X min-1. The 4 and 15 mg X min-1 infusion rates into the fetal jugular vein induced a significant decrease (p less than 0.05) in maternal uterine vein 13,14-dihydro-15-keto-prostaglandin F2 alpha plasma concentrations. These concentrations decreased from 669.3 +/- 161.3 pg X ml-1 (mean +/- SD) before infusion to 306.5 +/- 104.0 pg X ml-1 after 3 hours of infusion at 4 mg X min-1 and from 744.2 +/- 256.8 to 105.0 +/- 24.2 pg X ml-1 at 15 mg X min-1. Significant changes in maternal uterine vein plasma 6-keto-prostaglandin F1 alpha and the 6-keto-prostaglandin F1 alpha/13,14-dihydro-15-keto-prostaglandin F1 alpha ratio occurred only at the 15 mg X min-1 infusion of antipyrine into the fetal jugular vein (p less than 0.05). Maternal uterine vein 6-keto-prostaglandin F1 alpha fell from 86.0 +/- 31.6 to 37.0 +/- 11.5 pg X ml-1 and the 6-keto-prostaglandin F1 alpha/13,14-dihydro-15-keto-prostaglandin F2 alpha ratio rose from 0.14 +/- 0.10 to 0.35 +/- 0.10. We conclude that: antipyrine at doses currently used to measure uterine and umbilical blood flows inhibits 13,14-dihydro-15-keto-prostaglandin F2 alpha production and infusion rates of antipyrine less than 1 mg X min-1 probably do not affect maternal prostaglandin metabolism. We therefore recommend that if this method is to be used for measuring blood flow, antipyrine infusion rates should be less than 1 mg X min-1.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Concurrent bromosulphophthalein and antipyrine administration to assess liver blood flow and hepatic enzymes in rats.

This study investigated the feasibility of using concurrent iv administration of antipyrine (15 mg/kg body weight) and bromosulphophthalein (BSP; 25 mg/kg) in the rat. Antipyrine is used as an index of hepatic drug metabolism and BSP is used to assess hepatic blood flow. Plasma concentrations of BSP were described using biexponential phases, while antipyrine plasma concentrations were monoexponential. No significant difference was observed between antipyrine pharmacokinetic parameters in concurrent BSP rats when compared with controls. There was also no significant difference between BSP pharmacokinetic parameters in concurrent antipyrine rats when compared with controls, except in the alpha value (P less than 0.05). This indicates that BSP distribution may be affected by concurrent antipyrine administration. Therefore, simultaneous administration of both substrates is not acceptable to study hepatic blood flow. Another iv combination dose (25 mg BSP/kg body weight, followed by 15 mg antipyrine/kg 0.5 hr later) and a dose of 15 mg antipyrine/kg body weight only was administered to rats pretreated with phenobarbital (90 mg/kg body weight) for 6 days. Pharmacokinetic parameters of BSP, beta, k21, k23 and plasma clearance, in the pretreated rats were significantly different from non-pretreated rats. No significant difference was observed in the pharmacokinetic parameters of antipyrine between the combination dose and antipyrine dose in the phenobarbital-pretreated rats. The half-lives of antipyrine in both pretreated groups decreased approximately by 70%, while the clearance increased four times compared with controls. The volume of distribution in these animals did not change as a result of phenobarbital pretreatment. This suggests that a 25 mg BSP/kg body weight dose followed by 15 mg antipyrine/kg 0.5 hr later may be a feasible approach to study liver blood flow, as well as hepatic efficiency in rats.

Animals↗
PubMedDate not supplied

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-1 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.

Aging↗
PubMed1980

Antipyrine metabolite formation in children in the acute phase of malnutrition and after recovery.

1. The plasma elimination rate of antipyrine and the urinary excretion of antipyrine and its primary metabolites 4-hydroxy-antipyrine, norantipyrine, 3-hydroxymethyl-antipyrine and 3-carboxyantipyrine were measured in five children in the acute phase of malnutrition and after recovery. The results were compared with those obtained in 3 normal children. 2. Upon nutritional rehabilitation antipyrine clearance increased from 0.65 +/- 0.14 ml min-1 kg-1 to 1.07 +/- 0.20 ml min-1 kg-1. 3. The urinary excretion of 4-hydroxy-antipyrine increased from 6.1 +/- 4.5 to 14.7 +/- 5.9%, norantipyrine from 8.8 +/- 5.7 to 14.3 +/- 5.4 and 3-hydroxy-methyl-antipyrine from 11.8 +/- 8.3 to 20.5 +/- 5.6% (% of dose/24h urine). Excretion of unchanged antipyrine decreased from 5.2 +/- 3.7 to 2.7 +/- 0.9% dose. The metabolite profile (ratio between the amounts of the various metabolites excreted) was not significantly different. 4. It is concluded that malnutrition decreases the rate of antipyrine metabolism, but it does not affect the three oxidative pathways differently.

Acute Disease↗
PubMed1986

Antipyrine clearance and metabolism in patients with psoriasis.

The kinetic parameters of antipyrine obtained from saliva samples and the appearance of major antipyrine metabolites (4-hydroxyantipyrine, norantipyrine and 3-hydroxymethylantipyrine) in urine samples were measured in 10 patients with psoriasis (six nonsmokers and four smokers) and in 20 healthy subjects (11 nonsmokers and nine smokers). The volume of distribution and total clearance of antipyrine were not significantly different between psoriatric patients and control subjects subdivided according to smoking habit. However, antipyrine half-life was significantly (P less than 0.05) shorter in nonsmoking psoriatrics than in nonsmoking controls. There were no significant differences in mean values for the amounts (% dose) and partial clearances for production of major antipyrine metabolites between non-smoking patients and non-smoking controls, between smoking patients and smoking controls, and between patients overall and controls overall. The total clearance of antipyrine and the partial clearances of antipyrine to its three main metabolites were significantly (P less than 0.05 to 0.01) greater in smoking controls than in nonsmoking controls, and the total clearance of antipyrine and the partial clearance to 4-hydroxyantipyrine were significantly (P less than or equal to 0.05) greater in smoking patients than in nonsmoking patients. These findings provide no evidence that psoriasis is associated with an alteration in hepatic microsomal monooxygenase activity, at least insofar as the formation of major antipyrine metabolites is concerned.

Aged↗
PubMed1979

A sensitive gas-chromatographic assay using a nitrogen-phosphorus detector for determination of antipyrine and aminopyrine in biological fluids.

A method using gas chromatography with organic nitrogen-sensitive detection is described for measurement of antipyrine and aminopyrine concentrations in biological fluids. The analysis was performed isothermally on 3% SP-2250 DB after alkalinized saliva was extracted into chloroform. Phenacetin served as internal standard. Low oral doses of antipyrine (1.0-1.8 mg/kg) and/or aminopyrine (2 mg/kg) were measured accurately in saliva of normal human subjects. The standard curves for antipyrine and aminopyrine were linear from 0 to 10 microgram/ml. The coefficient of variation, determined at a salivary concentration of 2 microgram/ml, was 1.7% for antipyrine and 2.4% for aminopyrine. Saliva concentrations obtained by this method in normal human subjects after either an oral dose of antipyrine (18 mg/kg) or aminopyrine (9 mg/kg) agreed closely with those determined by the flame ionization gas-chromatographic method used to measure higher concentrations of antipyrine and aminopyrine. Antipyrine (1.8 mg/kg) administered concomitantly with aminopyrine (1 mg/kg or 2 mg/kg) to normal male volunteers prolonged mean saliva antipyrine half-life by about 25-33% compared to values obtained when these same subjects received the same dose of antipyrine alone.

Adult↗
PubMed1981

Influence of the genetically controlled deficiency in debrisoquine hydroxylation on antipyrine metabolite formation.

The influence of the genetically controlled deficiency in debrisoquine hydroxylation on antipyrine metabolite formation was studied by giving 500 mg antipyrine to 14 extensive and 10 poor metabolizers of debrisoquine. The pharmacokinetics of antipyrine were determined on the basis of the saliva concentration time curve and the cumulative urinary excretion of 4-hydroxyantipyrine, norantipyrine, 3-hydroxymethyl-antipyrine, and 3-carboxyantipyrine was measured for 32 h following drug administration. Antipyrine elimination half-life, volume of distribution, and total clearance were almost equal for the two groups. Significant differences in the excretion of antipyrine metabolites were not observed, except for 3-hydroxymethyl-antipyrine which was excreted in poor metabolizers about 30% less than in extensive metabolizers (p less than 0.01). However, this difference only reached borderline significance (p less than 0.1) when clearance values for production of this metabolite were calculated. It is concluded that different species of the drug-oxidizing enzymes (cytochrome P-450 system) are involved in the metabolism of debrisoquine and antipyrine. Possibly the enzyme responsible for hydroxylating debrisoquine is partly involved in the formation of 3-hydroxymethyl-antipyrine.

Aging↗
PubMed1992

Evidence of significant absorption of antipyrine from urinary bladder of rats.

We examined the in vivo absorption and pharmacokinetics of antipyrine, a base that is unionized at physiologic pH, from the urinary bladder of adult female Fischer rats. The clearance of an i.v. dose of antipyrine (25 mg/kg) was found to vary considerably between animals, which is consistent with the literature data. Therefore, it was necessary to simultaneously determine drug clearance and bladder absorption in the same animal. This was accomplished by giving concomitantly an i.v. dose of [14C]antipyrine (2.5 muCi, about 90 micrograms/kg) via a jugular vein catheter and an intravesical dose of unlabeled antipyrine (33 mg/kg) via a urethral catheter. Unlabeled antipyrine was detected in plasma, indicating the absorption of antipyrine into systemic circulation. The bioavailability of the intravesical dose was calculated using the clearance of [14C]antipyrine and the plasma concentrations of unlabeled antipyrine. The intravesical dose was withdrawn through the urethral catheter after 90 min. To minimize mechanical manipulation and damage, the bladder was not rinsed. This may have caused the incomplete recovery of the unabsorbed dose; about 65 +/- 18% (mean +/- S.D.) of the dose was recovered at 90 min. Maximal plasma concentrations were achieved at 10 to 48 min after removal of the intravesical dose, which is consistent with a continued absorption of the residual dose. The intravesical bioavailability was variable between animals, with an average of 11.6 +/- 6.4% (mean +/- S.D.; range, 4.1-19.2%). In conclusion, these data demonstrate that neutral drugs such as antipyrine are absorbed from the bladder, that the extent of absorption is variable and that the urinary bladder may be a site of significant re-entry of drugs into the systemic circulation.

Animals↗
PubMed1985

Plasma pharmacokinetics of adriamycin and antipyrine and its relation to the therapeutic and toxic effects.

After a simultaneous administration of adriamycin and antipyrine to 19 tumor patients, the plasma kinetics of both drugs, the therapeutic effect and the reaction to white blood cells were determined. Antipyrine was given orally at a dose of 875 mg, whereas adriamycin was administered by means of intravenous infusion for 20 min at 60 mg/m2. This application was repeated in eight patients after three weeks. Nine patients had a normal liver function. In ten patients, slight increases were found in individual liver function parameters. All patients were free from metastases of the liver and had bilirubin levels within the normal range. Antipyrine followed an open one-compartment model, whereas adriamycin followed an open two-compartment model. In the mean, t1/2 el and Cl tot of antipyrine were found to be 16.1 h and 32.9 ml/min, t1/2 beta and Cl tot of adriamycin were 23.1 h and 877 ml/min. For antipyrine and adriamycin, these parameters varied interindividually by the factors 2.8 and 3.1, respectively. No correlations were found between the liver function parameters, and the kinetic elimination parameters and the areas under the curves of both drugs. However, significant positive correlations were found to exist between t1/2 el antipyrine and t1/2 beta adriamycin and between the areas under the curves of the two drugs. A relationship between the AUC adriamycinol/AUC adriamycin ratio (which was 0.52 in the mean) and the antipyrine elimination rate did not exist. As compared to 12 persons with no response or progression, the seven patients with partial or complete response had a significantly higher AUC and a significantly lower Cl tot of adriamycin. As compared to the patients with elimination half-life values of less than 20 h, five patients with antipyrine elimination half-life values of more than 20 h had a significantly longer adriamycin elimination beta-phase and a stronger depressive effect on the white blood cells. The results obtained suggest that the antipyrine kinetics in patients with normal or slightly impaired liver function is a useful parameter for an assessment of the depression of white blood cells and the dose adjustment for adriamycin.

Administration, Oral↗
PubMedDate not supplied

Assessment of total body water in hemodialysis patients by a single oral dose of antipyrine.

Accurate determination of total body water in hemodialysis patients is important for calculation of the amount of fluid excess that should be removed by ultrafiltration, and for dialysis prescribing by KT/V. Indirect methods using 0.6 x body weight or pre and post serum urea concentrations are inaccurate and determination by tritiated water space requires the use of radioactivity. The authors measured the volume of distribution for antipyrine that is distributed in body water, and compared it to tritiated water space in hemodialysis patients. Sixteen patients on hemodialysis were given 500 mg antipyrine and saliva samples were collected at fixed time points. Concentrations of antipyrine in saliva were measured by high pressure liquid chromatography. Volume of distribution for antipyrine was calculated by pharmacokinetic methods. Fluid excess was determined as the difference between tritiated water space or volume of distribution for antipyrine and ideal total body water measured anthropometrically. Total body water as the volume of distribution for antipyrine was 24.8 to 61.5 (mean 44.0 +/- 10.3) L, or 68% of body weight, and tritiated water space 27.0 to 56.6 L (43.6 +/- 7.7), 67% of body weight. Volume of distribution for antipyrine correlated well with tritiated water space (r = 0.997 and p = 0.001). Fluid excess calculated from tritiated water space was between 2.5 and 12.4 (6.0 +/- 4.0) L, and from volume of distribution for antipyrine -0.7 to 13.3 (5.7 +/- 5.1) L (r = 0.80, p = 0.001). The authors conclude that by using a single oral dose of antipyrine, one can simply and accurately measures total body water in hemodialysis patients.

Administration, Oral↗
PubMed1992

Antipyrine metabolism in patients with liver metastases from colorectal cancer.

BACKGROUND: The influence of cancer on antipyrine metabolism is under debate. METHODS: To assess the functional activity of a liver with solid metastases from primary colorectal cancer, antipyrine metabolism was studied after the drug was administered orally (18 mg/kg body weight) to 55 healthy volunteers, 62 patients with well-compensated cirrhosis, and 42 patients with small (Class A) or massive (Class B) metastatic liver involvement. RESULTS: In patients with cancer, antipyrine clearance (0.472 +/- 0.177 ml/min/kg) was similar to that in healthy volunteers (0.456 +/- 0.198 ml/min/kg) and significantly higher than in those with cirrhosis (0.259 +/- 0.17 ml/min/kg, P less than 0.001). There was no difference in antipyrine pharmacokinetics between Class A and B involvement. In the entire population, antipyrine clearance was correlated with serum albumin levels (r = 0.294, P = 0.0002) and prothrombin activity (r = 0.416, P = 0.001). This positive correlation was not present when only the neoplastic group was considered. No correlation was found between antipyrine clearance and alkaline phosphatase levels. In patients with cancer, no relationship was found between antipyrine clearance and carcinoembryonic antigen and lactic dehydrogenase levels. CONCLUSIONS: These results show that patients with livers largely replaced by solid metastases are able to metabolize antipyrine to the same extent as healthy subjects.

Adult↗
PubMed1976

Antipyrin clearance in homozygous beta-thalassemia.

Serum half-lives for antipyrine were normal or shorter than normal in 19 subjects between 7 and 23 yr of age with beta-thalassemia major. The mean antipyrine serum half life (+/-SE) for the group as a whole was 8.5 +/- 0.6 hr. The mean antipyrine half-lives (t1/2) for the younger subjects were within the range reported for normal children, while the mean t1/2 for the older males approached the values reported for normal adult males. The mean t1/2 for the older females was shorter than has been reported for normal adult females. The mean apparent volume of distribution for antipyrine (+/-SE) in the subjects with thalassemia was 0.69 +/- 0.01 L/kg. Thus, total body water appears to be increased in thalassemia. The mean metabolic clearance rate for antipyrine (+/-SE) in the group as a whole (1.07 +/- 0.08 ml/min/kg) is substantially higher than the metabolic clearance rates for antipyrine reported in normal adults. Thus, the relatively short t1/2s of antipyrine in subjects with thalassemia are attributable to rapid rates of clearance of the drug. The data indicate that antipyrine clearance is unimpaired in patients with thalassemia despite evidence of liver damage and iron overload. Our study supports the proposition that hepatic microsomal hemoprotein synthesis is not adversely affected in homozygous beta-thalassemia.

Adolescent↗
PubMed1984

Effect of renal failure and bis(2-ethylhexyl) phthalate pretreatment on the disposition and metabolism of antipyrine in the rat.

Renal failure patients undergoing hemodialysis are regularly exposed to phthalate plasticizers leached from dialysis tubings. Previous studies have shown that antipyrine is eliminated more rapidly in chronic renal failure patients compared with normal individuals. Therefore, the effect of bis(2-ethylhexyl) phthalate on the metabolism of antipyrine was investigated in normal and renal failure rats. In normal animals, the elimination kinetics of an intravenous dose of antipyrine (20 mg/kg) was determined before and after 14 days of peroral treatment with 2 mL/kg/d of bis(2-ethylhexyl) phthalate. The plasma clearance of antipyrine increased markedly after bis(2-ethylhexyl) phthalate treatment. There was a corresponding decrease in the elimination half-life of antipyrine, whereas the apparent volume of distribution was not affected. Both liver weight and hepatic cytochrome P450 content increased following exposure to bis(2-ethylhexyl) phthalate, indicating the induction of hepatic microsomal enzymes. The fractional urinary recovery of the N-demethyl, 4-hydroxy, and 3-hydroxymethyl metabolites of antipyrine was not altered, suggesting that all three oxidative pathways were induced to the same extent. Renal failure alone did not affect the elimination kinetics of antipyrine. However, antipyrine clearance was induced to a greater extent by bis(2-ethylhexyl) phthalate treatment in the renal failure rats as compared with the control animals. The potential for phthalate plasticizers to alter hepatic drug metabolism in hemodialysis patients should be considered.

Animals↗
PubMed1995

Antipyrine disposition in obesity: evidence for negligible effect of obesity on hepatic oxidative metabolism.

Following an overnight fast and 2 days of abstention from caffeine, a single 1.0-g oral dose of antipyrine was administered to 20 obese but otherwise healthy subjects (group A) and 11 healthy volunteers (group B). Weight, Body Mass Index (BMI) and % of Ideal Body Weight (IBW) were significantly greater in the obese than in the lean group. (Mean 110.4 vs 62.7 kg; 38.5 vs 22.3 kg.m-2 and 181 vs 106% respectively). In a subgroup of 6 obese subjects (group C) antipyrine was given again 11.3 months later after a 29.8 kg mean weight loss. Antipyrine apparent volume of distribution (V) and elimination half-life (t1/2) were significantly greater in the obese than in the lean group (V 49.9 vs 34.3 l respectively; t1/2 15.5 vs 12.0 h respectively), but its clearance rate (CL0) values were similar. V corrected for total body weight was significantly reduced in group A than in group B (0.45 vs 0.55 l.kg-1 respectively). Stratified comparison of antipyrine pharmacokinetics between obese and lean subjects according to age, gender and smoking habits did not alter the overall results. In group C, weight reduction was associated with a significant decrease in antipyrine V (from 51.8 to 47.5 l) and t1/2 (from 15.1 to 12.7 h), and a non-significant increase in antipyrine CL0. We conclude that in severely obese subjects, antipyrine total V is mildly increased but V corrected for total body weight is significantly decreased. In addition, obesity is associated with a slight prolongation of antipyrine t1/2 whereas its CL0 is unaltered. These findings may indicate that obesity, even in its extreme form, has a negligible effect on the oxidative metabolic capacity of the liver.

Adolescent↗
PubMed1982

Studies of the different metabolic pathways of antipyrine in man. Oral versus i.v. administration and the influence of urinary collection time.

The pharmacokinetics of antipyrine in plasma and saliva, and urinary excretion of its major metabolites, were studied following i.v. and oral administration of antipyrine 500 mg to 6 healthy volunteers. Data from both plasma and saliva showed that the oral bioavailability of antipyrine given as an aqueous solution was complete. The saliva/plasma concentration ratio was constant with time from about 3 h onwards, with a mean value of 0.87 after oral and 0.91 after i.v. administration. It is concluded that the pharmacokinetic parameters of antipyrine can be satisfactorily established on the basis of salivary data, although the volume of distribution and clearance values are then slightly too high. After i.v. administration, 3.8 +/- 1.9% of the dose was excreted in urine as unchanged antipyrine in 48 h, 24.9 +/- 6.3% as 4-hydroxyantipyrine, 16.5 +/- 3.2% as norantipyrine, 13.0 +/- 2.2% as 3-hydroxymethyl-antipyrine and 5.8 +/- 1.0% as 3-carboxy-antipyrine. No significant differences were observed following oral administration. The half-lives calculated from the linear part of the urinary excretion rate curves of the metabolites were about the same for oral and i.v. administration, and were of the same order of magnitude as the elimination half-life of parent drug in plasma and saliva. It is important for determination of the ultimate metabolite ratio that urine is collected for at least 36 h, because there is a delay in the excretion of 3-hydroxymethyl-antipyrine in urine.

Administration, Oral↗
PubMed1993

Metabolism of antipyrine in vivo in two rat models of liver cirrhosis. Its relationship to intrinsic clearance in vitro and microsomal membrane lipid composition.

Antipyrine metabolism depends on at least three isoenzymes of cytochrome P450 forming the main metabolites 3-OH-, 4-OH- and norantipyrine. We investigated to what extent antipyrine clearance and metabolite formation are impaired in two models of liver cirrhosis in the rat, namely micronodular cirrhosis induced by chronic exposure to phenobarbital/CCl4 and biliary cirrhosis induced by bile duct ligation. Salivary antipyrine clearance was decreased to a similar extent in cirrhosis induced by CCl4 and bile duct ligation (-35%). Clearance for production of 3-OH-antipyrine was decreased in both models, while 4-hydroxylation was maintained. Metabolic clearance of both 3-OH-antipyrine and 4-OH-antipyrine in vivo correlated with their clearance in vitro (r = 0.658 and r = 0.583) but not with that of norantipyrine. The microsomal cholesterol content was increased by 16% and 90% in CCl4 and bile duct-ligated cirrhotic rats (P < 0.001), respectively. Membrane fluidity, expressed as the ratio of phospholipids to cholesterol, correlated with the in vivo clearance for production of norantipyrine (r = 0.841) but not of 3-OH- or 4-OH-antipyrine, while clearance in vitro was not related to altered lipid composition. Our results demonstrate that the cytochrome P450 isoenzymes responsible for the different pathways of antipyrine metabolism are affected to different extents by cirrhosis. Alterations in intrinsic clearance explain only part of the loss of hepatocellular function. Altered lipid composition contributes to this loss of function but other factors, among them loss of hepatocytes and changes in microcirculation, could be more important determinants of the decrease in xenobiotic metabolism in cirrhosis.

Animals↗
PubMed1982

A non-invasive method for the study of hepatic drug metabolism in rodents: antineoplastic drug effects on antipyrine metabolism in mice.

A rapid, sensitive and simple high pressure liquid chromatography (HPLC) method is described for the direct analysis of antipyrine in saliva. The detection limit was found to be 1.0 ng/ml of sample, lower than any previously reported method. Accuracy and precision were maintained with as little as 0.5 microliter of saliva. Thus the rate of elimination of antipyrine has been monitored non-invasively in rats and for the first time in mice. The antipyrine half-life was found to be 28.9 +/- 4.0 (S.E.M.) min and 111 +/- 20 min in mice and rats, respectively. In mice single i.p. doses of 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) (30 mg/kg) produced increases in antipyrine half-life, up to 28 days post-treatment. The maximum effect of BCNU was observed on day 7 with an antipyrine half-life of 74.4 +/- 15.7 min. Phenobarbital induction lowered the antipyrine half-life in controls to 12.6 +/- 1.2 min. An enhanced inductive effect was observed in BCNU-treated mice: BCNU-treated, phenobarbital-induced mice displayed a half-life for antipyrine of 7.4 +/- 0.6 min on day 21 post BCNU dose. These effects could not be attributed to changes in absorption of antipyrine in BCNU-treated mice.

Aminopyrine↗