The pharmacokinetics of antipyrine and three of its metabolites in the rabbit: intravenous administration of pure metabolites (original) (raw)
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The Effect of Age and Sex on Metabolism and Urinary Excretion of Antipyrine
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 1998
Background. Drug-metabolizing capacity is generally reduced in the elderly. The purpose of this investigation was to study antipyrine clearance and metabolite excretion in old subjects of both sexes. Methods. Saliva clearance of antipyrine and the production clearances of antipyrine metabolites were studied in young and elderly volunteers of both sexes. Seventy-six elderly subjects (mean age 81 years) were compared with a group of 24 young subjects (mean age 29 years). Results. After oral administration, salivary antipyrine clearance declined with age in both males and females, whether or not this variable was corrected for weight, and antipyrine half-life was significantly prolonged in elderly groups of either sex. The percentage urinary excretion of the antipyrine metabolites (hydroxymethylantipyrine, HMA; norantipyrine, NORA; and 4-hydroxyantipyrine, OHA) was reduced at 48 h in the elderly compared to young subjects by 23%, 31%, and 10%, respectively, in males, and by 41%, 41%, and 24%, respectively, in females. The formation clearance of HMA was reduced by 47% in males and by 52% in females. NORA clearance declined by 42 and 56%, respectively, in males and females. A decrease of 30% in males and 44% in females was observed in OHA clearance. Conclusions. The findings suggest that aging leads to altered disposition of antipyrine in both males and females and that the main metabolic pathways of the compound are not different in the elderly.
Journal of Chromatography A, 1988
Antipyrine and aminopyrine are routinely used as model compounds in the study of hepatic microsomal mixed-function oxidase activity in vitro and in vivo'-3 and 4-aminoantipyrine is one of the metabolites of aminopyrine. Antipyrine, aminopyrine and their metabolites can be determined in biological fluids using various chromatographic methods. Thin-layer chromatographic procedures4s5 have poor sensitivity and yield only semi-quantitative results. Gas chromatography6*7 and gas chromatography-mass spectrometry'*' exhibit sufficient sensitivity and selectivity, but require derivatization. High-performance liquid chromatography (HPLC) with spectrophotometric detection has found wide use in assaying these compounds in plasma, urine and liver microsomes'-i4. However, biological fluids contain many components that interfere in photometric detection and thus a sample purification step is required prior to the analysis, especially with urine samples. One of the advantages of voltammetric detection is its high selectivity, which often considerably simplifies the sample pre-treatment". This paper describes a simple HPLC method with amperometric detection for determining antipyrine and 4-aminoantipyrine in human urine, which does not require a prepurification step.
Effect of deltamethrin on antipyrine pharmacokinetics and metabolism in rat
Archives of Toxicology, 1991
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 [3 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 <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.
Sex difference in antipyrine 3-hydroxylation
Biochemical Pharmacology, 1990
Antipyrine metabolism depends on at least three isoenzymes of cytochrome P450 forming the main metabolites 3-OH-, 4-OH-and norantipyrine. We investigated to which extent antipyrine clearance and metabolite formation in vivo correlate with metabolite formation by microsomal fractions in vitro. The influence of sex was investigated in two rat strains. Antipyrine clearance in saliva was determined in lO-month-old Sprague-Dawley and Dark Agouti rats of either sex. Antipyrine and its metabolites in urine and microsomes were measured by a new HPLC method after solid phase or liquid extraction. Antipyrine clearance was 46% higher in males than in female rats. This was associated with a 40% higher urinary excretion of 3-OH-antipyrine in the male rats, the other metabolites being excreted to a similar extent. This higher production of 3-OH-antipyrine in vivo was paralleled by a higher intrinsic clearance in vitro while no sex difference in intrinsic clearance for the formation of the other metabolites was seen. The correlation between in vivo and in vitro metabolic clearance for 3-OH-antipyrine was good (r = 0.75) but unconvincing for 4-OH-(r = 0.49
Effect of ciprofloxacin on antipyrine pharmacokinetics and metabolism in rats
Antimicrobial Agents and Chemotherapy, 1990
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 si...
Metabolism of drugs and carcinogens in man: Antipyrine elimination as an indicator
Clinical Pharmacology & Therapeutics, 1979
The suitability oJ the most commonly used "prototype" drug, viz, antipyrine, in predicting drug and carcinogen metabolism was evaluated, by studying in vivo antipyrine elimination rate (Ke) and in vitra metabolism oJ drugs and carcinogens in liver preparations in the same individuals. Our subjects were 20 adult males undergoing abdominal surgery Jor gastrojejunostomy, although antipyrine Ke could be studied in onl}' 16 subjects. Correlations oJ the various in vitra-in vivo parameters were positive between the parameter pairs: in vivo antipyrine Ke-in vitro benzopyrene hydroxylase; benzopyrene hydraxylase-aniline hydraxylase; and benzopyrene hydraxylase-y-glutamyl transJerase. Aminopyrine demethylase did not correlate with any oJ the parameters studied. The degree oJ correlation between antipyrine Ke and benzopyrene hydroxylase was statistically significant but was not satisJactor}' Jor predictive purposes. Our study indicates some oJ the problems and limitations oJ in vivo-in vitro comparisons and confirms earlier doubts on the useJulness oJ antipyrine as a "prototype" drug Jor predicting drug and carcinogen metabolism in man.
Accuracy of the one-sample method for determination of antipyrine clearance in elderly subjects
Journal of Pharmaceutical and Biomedical Analysis, 1996
The purpose of this study was to evaluate the validity of the one-sample abbreviated method for determination of the pharmacokinetic parameters of antipyrine in the elderly. Antipyrine pharmacokinetics were studied in 15 elderly women (mean age 86 years). Antipyrine (1 g) was administered orally and pharmacokinetic parameters were determined by the one-sample (24 h) and multiple-sample (3, 6, 9, 12 and 24 h) methods. Mean antipyrine clearance for the one-sample study (19.72 + 1.51) was almost identical to that obtained with the multiple-sample approach (20.73 + 1.57), and the two methods were very well correlated (r = 0.989). Relative standard deviations between individual clearances values for multiple-sample vs. one-sample studies averaged 1.6%. Values of elimination half-life were likewise very similar for the abbreviated (17.41 + 1.21) and complete (17.99 + 1.09) methods, with a significant correlation (r = 0.857). Although values were underestimated by 10%, in the one-sample approach, no difference in the volume of distribution with the multiple-sample study was observed. When the unbiased volume of distribution value was determined from the total elimination curve against time, the influence of biased volume of distribution resulted in a 5.1% deviation in antipyrine clearance in the one sample method. The findings indicate that antipyrine pharmacokinetic parameters can be estimated with reasonable precision and accuracy in the elderly using a simplified one-sample procedure. and is extensively metabolized by the cytochrome P-450 liver enzymes. Antipyrine shows a negligible protein binding and its elimination is not limited by liver blood flow, which declines with age. Changes in hepatic oxidative capacity contribute to altered responses to drugs in the elderly, and specific information concerning hepatic function can be obtained by estimation of antipyrine kinetic parameters [1]. In a number of studies 0731-7085/96/$15.00
Pharmacokinetic parameters of antipyrine in dog after hepatectomy
Biopharmaceutics & Drug Disposition, 1995
Pharmacokinetic studies with antipyrine were carried out on beagle dogs to determine the consequence of hepatectomy on hepatic drug metabolizing capacity, the rate of hepatic regeneration, and the possible beneficial effect of hepatocellular transplantation.