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 181vs 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 (t _1/2) were significantly greater in the obese than in the lean group (V 49.9 vs 34.3 l respectively; t _1/2 15.5 vs 12.0 h respectively), but its clearance rate (CL_o) 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 t _1/2 (from 15.1 to 12.7 h), and a non-significant increase in antipyrine CL_o.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 t _1/2 whereas its CL_o 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.     

Antipyrine metabolite kinetics in rats: studies on dose and time dependence

Antipyrine metabolite kinetics have been investigated in the rat with respect to dose and time dependence. The metabolic pathways, 4-hydroxylation, benzylic oxidation, and N-demethylation, are of equal quantitative importance (approximately 20 per cent of dose) and show no dose dependence over the range 25-500 mg kg-1. By using [N-methyl-14C]-antipyrine, the single carbon fragment lost by N-demethylation may be monitored as 14CO2. Serial sampling of 14CO2 exhalation rate provides a half-life estimate which, according to theoretical principles, reflects the antipyrine plasma half-life. When both half-lives were measured in the same animals a statistically significant correlation was evident. At doses of 250 mg kg-1 and 500 mg kg-1 there is an increase in CER half-life (218 and 303 min respectively) when compared to a dose below 100 mg kg-1 (152 min). The metabolite formation rate constants are decreased accordingly at the high doses but are invariant over the dose range 25-100 mg kg-1. Although inter-rat variation in antipyrine metabolite kinetics was substantial, intra-rat variability was small. The noninvasive nature of determining antipyrine metabolite kinetics via breath and urine analysis provides a potentially useful animal model system to investigate the factors influencing hepatic mixed function oxidase activity in vivo.     

Disposition and Oxidative Metabolism of Antipyrine in the Rat

Abstract The main routes of excretion of antipyrine-N-methyl-¹⁴C and the role of oxidation in the metabolism of antipyrine were studied in the rat. After an intraperitoneal dose of 15 mg/kg ¹⁴C-antipyrine (1.0-1.5 uCi ¹⁴C), 74.2% of the radioactivity was found in the urine, 2.5% appeared in the faeces and 2.6% was recovered from expired CO₂ after 48 hrs. Most of the radioactivity (98%) was excreted during the first 24-hrs. The cumulative excretion of radioactivity in the bile amounted to 18% of the dose in 24 hrs. Only 1-2% of the radio activity in the urine represented unchanged antipyrine. Antipyrine was extensively metabolized by oxidation followed by conjugation. In urine 3-CH₂OH-antipyrine and 4-OH-antipyrine (unconjugated and conjugated) accounted for 35 and 18% of the radioactivity, respectively. 3-carboxy antipyrine represented 17% of the radioactivity. The corresponding figures for bile were 51,19 and 9%. In addition, the non-radioactive N-demethylated metabolite, nor-antipyrine, was found. The quantitation of N-demethylation based on radioactivity recovered from expired CO₂ suggested that at least 2.6% of antipyrine was metabolized by this pathway. The results show that antipyrine was extensively oxidized in the rat. Thus, in this species, antipyrine meets a fundamental requirement of a model compound for the study of factors influencing drug oxidation in vivo.     

Dextromethorphan Pretreatment Induces Antipyrine Clearance in the Rat

Numerous agents that undergo extensive first-pass metabolism have been shown to inhibit oxidative drug metabolism. To examine whether this effect is related to the chemical structure or pharmacokinetic characteristics of the inhibiting agent, we determined the effect of dextromethorphan (a compound which exhibits pharmacokinetic similarities to, but is chemically dissimilar from, previously studied agents) on the disposition of antipyrine. A single oral dose of dextromethorphan hydrobromide, 100 mg/kg, 1 hr prior to antipyrine administration had no significant effect on the pharmacokinetics of this model substrate. The administration of dextromethorphan at the same dose twice daily for 3 days and an additional dose 1 hr prior to antipyrine administration resulted in a 33% increase in the clearance of antipyrine. These data indicate that dextromethorphan is capable of inducing hepatic microsomal enzymes. Studies are needed to determine if this effect also occurs upon chronic administration in humans. These data suggest that the pharmacokinetic characteristic of extensive first-pass metabolism is not necessarily associated with inhibition of drug metabolism.     

Effect of Hydralazine on the Elimination of Antipyrine in the Rat

The concomitant administration of hydralazine with metoprolol or propranolol substantially increases the oral bioavailability of these beta-blockers, presumably via reduction of the first-pass effect. It has been suggested that this effect may be secondary to a decrease in the intrinsic clearance of propranolol, possibly by inhibition of oxidative metabolism. To examine the possibility that hydralazine alters oxidative metabolism in vivo, the effect of hydralazine on the pharmacokinetics of antipyrine was examined in the rat. The oral administration of hydralazine hydrochloride, 7.5 mg/kg, 15 min prior to antipyrine administration reduced antipyrine clearance from 9.66 ± 1.18 to 8.19 ± 0.76 ml/min/kg (P < 0.05). Hydralazine was observed to cause substantial hypothermia. The study was repeated in temperature-regulated animals and no alteration in antipyrine clearance was found. Two doses of hydralazine in temperature-regulated rats also failed to alter antipyrine clearance. Thus, it appears that the effect of hydralazine on antipyrine clearance is secondary to the hypothermic effect of hydralazine and not due to a direct inhibition of cytochrome P-450-mediated enzyme activity.     

Effect of Amiodarone and Desethylamiodarone on the Pharmacokinetics of Antipyrine in the Rat

The effect of amiodarone on hepatic drug metabolism in vivo was examined in the rat using antipyrine as a model substrate. Pretreatment with oral amiodarone hydrochloride, 100 mg/kg/day, for 5 days resulted in a 19% reduction in antipyrine clearance and a 22% increase in half-life. The administration of single oral doses of amiodarone hydrochloride, 100 mg/kg, 1 or 5 hr prior to antipyrine administration had no significant effect on antipyrine pharmacokinetics. The administration of a single intravenous dose of amiodarone hydrochloride, 50 mg/kg, reduced antipyrine clearance by 32% and increased the half-life by 46%. The desethyl metabolite of amiodarone was also found to reduce antipyrine clearance (21%) after a single oral dose of 100 mg/kg.     

Antipyrine metabolite formation and excretion in patients with chronic renal failure

Summary In the present study the influence of chronic renal insufficiency on antipyrine clearance, metabolite formation and excretion was investigated in 8 patients. After oral administration of antipyrine, the parent compound, its metabolites and their conjugates were assayed in plasma and urine. Besides the parent drug, 3-hydroxymethylantipyrine (HMA) was present in plasma in the free and conjugated forms, whereas 4-hydroxyantipyrine (OHA) and norantipyrine (NORA) were found only in the conjugated form. The same was true for urine. The plasma concentrations of these metabolites are too low to be measured in subjects with normal renal function.Plasma antipyrine clearance in the patients was in the same range as in healthy subjects. Investigation of metabolite kinetics, however, revealed that the rate of formation of NORA was preferentially decreased, whereas that of OHA and HMA were unaltered. Renal clearance of the metabolites of antipyrine was severely impaired in patients with renal insufficiency, and the resulting accumulation made it possible for the first-time to measure the antipyrine metabolites in plasma. Mean residence times of metabolites were longer than that of the parent compound. Renal clearances of the conjugates were correlated with the creatinine clearance, but were somewhat higher. Renal clearance of free HMA was lower and was also correlated with creatinine clearance.The mean clearance for glucuronidation of HMA was 93.1 ml/min. The results suggest that in healthy subjects Phase I metabolism is the rate-limiting step in the elimination of antipyrine, which is essential for its application as a model drug in metabolism studies.     

Vascular reactivity in perinatally undernourished rats

Adult rats submitted to perinatal protein deprivation (from day 14 of fetal life till 50 days of age) followed by a longer phase of nutritional recovery on balanced laboratory chow, showed a significant decrease of the pressor response elicited by noradrenaline and adrenaline, an effect that persisted after ganglionic blockade by hexamethonium. However, the effects of serotonin, acetylcholine, angiotensin II and vasopressin on blood pressure did not differ from those in the controls. Cumulative dose-response curves to noradrenaline and methoxamine on the circular contraction of isolated iliac arteries showed a significant shift to the right, together with a reduction in the maximal contraction. No significant difference in the maximal contraction elicited by Ba2+ was observed in experimental preparations as compared with controls. These results suggest the development of a specific subsensitivity to sympathetic drugs in the vascular bed as a consequence on undernutrition during perinatal life.     

Effect of miocamycin on theophylline kinetics in children

Summary The interaction between a new macrolide antibiotic, miocamycin, and theophylline was evaluated in a single cross-over study in 5 asthmatic children. Each patient received a single dose of theophylline (4.3 mg/kg) delivered in 15 min using a constant-rate infusion pump, immediately before and after a 10 day course of miocamycin 17.5 mg/kg b.d. The pharmacokinetics of theophylline were calculated for each phase of the study. The elimination rate constant (3.92 vs 3.74 h^–1), the mean total body clearance (1.71 vs 1.8 ml·min·kg^–1) and the mean apparent volume of distribution (0.57 vs 0.58 l·kg^–1) did not differ. The result can be explained by the inability of the antibiotic to form inactive cytochrome P-450 metabolite complexes which can interfere with the metabolism of theophylline. Thus, miocamycin can safely be administered to asthmatic children requiring theophylline treatment, when they have an infection due to susceptible pathogens.     

HPLC法测定胎盘灌流液中安替比林浓度

目的:建立测定胎盘灌流液中安替比林浓度的方法。方法:样品采用液-液萃取预处理后,以高效液相色谱法测定。色谱柱为WatersSymmetryC18,流动相为甲醇∶0.05mol·L-1磷酸氢二钠缓冲液(pH=6.5)=70∶30,内标为非那西丁,流速为1mL·min-1,紫外检测波长为254nm。结果:安替比林检测浓度在1.095～20mg·L-1范围内线性关系良好(r=0.9996);低、中、高3种浓度质控样品的日内RSD分别为5.03%、1.49%、1.53%,日间RSD分别为2.99%、1.01%、0.75%;平均方法回收率为97.19%～103.11%。结论:本方法简便可靠、专属性好、精密度高,可用于胎盘灌流液中安替比林浓度的测定。     

Effect of Isoflurane Anesthesia on Antipyrine Pharmacokinetics in the Rat

Pharmaceutical Research -     

Drug Metabolism and Laboratory Anesthetic Protocols in the Rat: Examination of Antipyrine Pharmacokinetics

Pharmaceutical Research -     

HPLC法同时测定米格来宁片中安替比林和咖啡因的含量

目的：采用高效液相法同时测定米格来宁片中安替比林和咖啡因的含量。方法：以C18化学键合硅胶为固定相，以甲醇-水（42：58）为流动相，检测波长为273nm。结果：安替比林平均回收率为100．30．4，RSD=0．52（n=6）；咖啡因为99．5％，RSD=0．73（n=6）。安替比林在98．2～147mg范围内；咖啡因在9．99-15．0mg范围内，进样量与峰面积值呈良好的线性关系。结论；方法简便、快速、结果准确。     

The interaction of cigarette smoking and chronic drug ingestion on human drug metabolism

1. Drug metabolism was assessed by the disappearance rate of antipyrine as measured in saliva. Results were expressed in terms of both clearance and half life. 2. Basal measurements of antipyrine disappearance rate were performed in seven non-smokers and six smokers. After administration of glutethimide 250 mg daily for 7 days a second measurement of antipyrine disappearance rate was made. 3. Glutethimide enhanced antipyrine metabolism in both smokers and non-smokers. The degree of change in both groups was similar. 4. A similar study was carried out with a smaller dose (125 mg) of glutethimide. There was no significant difference between smokers and non-smokers.5. The data are consistent with smoking and chronic drug ingestion having additive effects on enhancement of hepatic drug metabolism.     

Metabolism of 14C-Antipyrine in Suspensions of Isolated Rat Liver Cells

Abstract Suspensions of liver cells isolated from perfused rat livers were incubated with antipyrine-N-methyl-¹⁴C. Antipyrine was eliminated by first-order kinetics during incubations for 3 hours with primary suspensions (parenchymal cells + non-parenchymal cells) and suspensions of purified parenchymal cells. Antipyrine concentrations were unchanged when incubated with suspensions of non-parenchymal cells, dead cells or medium only. At the end of incubation period, 4-OH-antipyrine and 3-CH₂OH-antipyrine were detected mainly as the glucuronide or sulphate conjugates, and evidence for the N-demethylation of antipyrine was also obtained. Half-lives for elimination of antipyrine in primary cell suspensions were not significantly different from the half-lives measured in parenchymal cell suspensions. This finding together with the lack of metabolism of antipyrine found in non-parenchymal cell suspensions suggest that oxidation and conjugation of antipyrine is mainly confined to the parenchymal cells. There was significant inhibition of antipyrine metabolism in primary suspensions by phenylbutazone (1.6 × 10^-3 M), dexamethasone (2 × 10^-4 M) and ethanol (1.3 × 10^-2 M, 0.75 %₀). We suggest that the use of primary suspensions of isolated rat liver cells provide a rapid and simple method for the study of factors influencing drug metabolism in the liver.     

Disposition of antipyrine in patients with extensive metastatic liver disease

Summary In the present study the effect of metastatic liver disease on hepatic drug metabolism has been examined by studying the pharmacokinetics of antipyrine and the urinary excretion of antipyrine and its three major metabolites (4-hydroxyantipyrine, norantipyrine, and 3-hydroxymethylantipyrine) in 12 patients with extensive metastatic liver disease, and in 12 matched healthy controls.In the patients total liver volume, the volume of the liver parenchyma, and the volume of the liver metastases were determined by computed tomography. The volume of liver metastases always exceeded 35% of the total liver volume.There were no significant differences between the patients and controls in plasma half-life, plasma clearance, or apparent volume of distribution of antipyrine.The cumulative urinary excretion of antipyrine and its three major metabolites was significantly lower in patients [44 (18)%] than in controls [71 (8)%]. The excretion of antipyrine itself was unchanged and the decrease in cumulative excretion was due to reduced excretion of the three metabolites.The results show that the activity of the hepatic mixed function oxidases was not impaired even in patients with extensive metastatic liver disease. This may be because liver metastases do not cause a corresponding reduction in the volume of normal hepatic parenchyma. The decreased urinary excretion of the three major metabolites of antipyrine, which are mainly glucuronidated, may have been due to an alteration in the process of conjugation.