EFFECT OF TURPENTINE-INDUCED INFLAMMATION ON THE DISPOSITION KINETICS OF PROPRANOLOL, METOPROLOL, AND ANTIPYRINE IN THE RAT

Plasma concentrations after oral administration of the high extraction drug propranolol are increased in patients and animals with inflammation. This could be due to increased serum propranolol binding, but also to decreased first-pass metabolism. We studied the pharmacokinetics of 3 drugs in control rats and in rats with turpentine-induced inflammation: propranolol, which is bound extensively to alpha 1-acid glycoprotein (alpha 1-AGP); metoprolol, another high extraction drug, but which is negligibly bound to alpha 1-AGP; and antipyrine, a low extraction drug, not bound to serum proteins. After IV administration of propranolol in rats with inflammation, systemic clearance, volume of distribution, and free fraction decreased, and the area under the curve (AUC) increased, whereas the half-life did not change. As the systemic clearance of a high extraction drug such as propranolol depends on hepatic blood flow only, a fall in hepatic blood flow or transition to a low extraction situation should be postulated. After oral administration of propranolol, the AUC was increased 20-fold in rats with inflammation; as the decrease in free fraction was only 4-fold, it can be concluded that a considerable decrease in hepatic intrinsic clearance was present. For metoprolol, in contrast to propranolol, after IV administration, no changes in pharmacokinetic parameters as a result of inflammation were observed. After oral administration, the AUC was increased about 4 times in rats with inflammation; as metoprolol is only negligibly bound to serum proteins, the increase in AUC can be attributed to a decrease in hepatic intrinsic clearance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Virtually Unaltered Permeability-Surface Area Products Imply Little Capillary Recruitment in Brain with Hypoxia

Objective : To test the capillary recruitment hypothesis for the brain with control and hypoxic rats. Methods : Local cerebral blood flow (LCBF) was sharply raised by respiring 10% O₂ (hypoxia). LCBF as well as local influx rate constants (K₁) and permeability-surface area (PS) products of ¹⁴C-antipyrine and ¹⁴C-3-O-methyl-d-glucose (30MG) were estimated for capillary systems in 44 brain areas. Results : With this testing, an increase in PS product would be suggestive of capillary recruitment. In all brain areas, LCBF was increased by 30–90% by hypoxia. Hypoxia modestly raised the influx of antipyrine in brain but did not appreciably alter its PS products. With hypoxia, K₁'s and PS products of 30MG were significantly lowered (5–25%) throughout the brain, and the blood levels of glucose were sizeably raised. The latter increase would diminish the transfer of 30MG across the blood-brain barrier by the hexose transporter because of increased glucose competition. By applying a glucose-concentration correction to the data, the apparent PS product of 30MG for the hypoxic group became equal to that for the controls, which agrees with the antipyrine PS product results. Conclusions : Hypoxia, thus, leads to virtually no increase in PS products and no capillary recruitment in brain, and elevates LCBF mainly, perhaps exclusively, by raising the velocity of flow through already perfused capillaries.     

A study of the factors affecting the metabolic clearance of quinine in malaria

Objective: To assess the factors that contribute to impaired quinine clearance in acute falciparum malaria. Patients: Sixteen adult Thai patients with severe or moderately severe falciparum malaria were studied, and 12 were re-studied during convalescence. Methods: The clearance of quinine, dihydroquinine (an impurity comprising up to 10% of commercial quinine formulations), antipyrine (a measure of hepatic mixed-function oxidase activity), indocyanine green (ICG) (a measure of liver blood flow), and iothalamate (a measure of glomerular filtration rate) were measured simultaneously, and the relationship of these values to the␣biotransformation of quinine to the active metabolite 3-hydroxyquinine was assessed. Results: During acute malaria infection, the systemic clearance of quinine, antipyrine and ICG and the biotransformation of quinine to 3-hydroxyquinine were all reduced significantly when compared with values during convalescence. Iothalamate clearance was not affected significantly and did not correlate with the clearance of any of the other compounds. The clearance of total and free quinine correlated significantly with antipyrine clearance (r _s = 0.70, P = 0.005 and r _s = 0.67, P = 0.013, respectively), but not with ICG clearance (r _s = 0.39 and 0.43 respectively, P > 0.15). In a multiple regression model, antipyrine clearance and plasma protein binding accounted for 71% of the variance in total quinine clearance in acute malaria. The pharmacokinetic properties of dihydroquinine were generally similar to those of quinine, although dihydroquinine clearance was less affected by acute malaria. The mean ratio of quinine to 3-hydroxyquinine area under the plasma concentration-time curve (AUC) values in acute malaria was 12.03 compared with 6.92 during convalescence P=0.01. The mean plasma protein binding of 3-hydroxyquinine was 46%, which was significantly lower than that of quinine (90.5%) or dihydroquinine (90.5%). Conclusion: The reduction in quinine clearance in acute malaria results predominantly from a disease-induced dysfunction in hepatic mixed-function oxidase activity (principally CYP 3A) which impairs the conversion of quinine to its major metabolite, 3-hydroxyquinine. The metabolite contributes approximately 5% of the antimalarial activity of the parent compound in malaria, but up to 10% during convalescence. Received: 20 December 1996 / Accepted in revised form: 9 April 1997     

多波长吸收度比值法测定安痛定注射液中氨基比林和安替比林

采用文献报道的多波长吸收度比值法，直接同时测定安痛定注射液中氨基比林和安替比林二者的含量。其平均回收率分别为：氨基比林９９．９４％，ＲＳＤ＝０．１５％；安替比林９９．５０％，ＲＳＤ＝０．９３％。     

Antipyrine clearance in chronic and neoplastic liver diseases: A study of 518 patients

Antipyrine metabolism is widely used as an index of the drug-metabolizing reserve of the liver. It is well known that metabolism of this drug is impaired in subjects with acute hepatitis or cirrhosis, but conflicting data have been reported regarding patients with chronic postinfectious hepatitis or liver cancer. We studied conventional liver-function parameters and antipyrine metabolism (antipyrine per o.s. 18mg/kg) in 518 subjects. One hundred and one patients had liver metastases (various primaries). Based on the number and size of lesions, the hepatic involvement was considered minimal in 47 and massive in 54 (groups B1 and B2, respectively). One hundred and two had chronic active hepatitis (CAH); 51 patients with histological evidence of fibrosis/early cirrhosis and 51 patients were without histological evidence of fibrosis/early cirrhosis. Ninety-two had histologically confirmed cirrhosis (group D), and the remaining 120 had cirrhosis and hepatocellular carcinoma (group E). The control group was composed of 103 subjects with healthy livers (group A). Antipyrine clearance (AP Cl) in CAH patients with fibrosis (0.246 ± 0.98 mL/min per kg) was similar to that observed in patients with cirrhosis (0.223 ± 0.148 mL/min per kg), and both values were significantly lower than that found in CAH patients without fibrosis (0.406 ± 0.159 mL/min per kg, P < 0.01). Antipyrine clearance in patients with liver metastases (0.426 ± 0.174 mL/min per kg) was similar to that of the healthy group (0.489 ± 0.210 mL/min per kg). Cirrhotics and cirrhotics with hepatocellular carcinoma (HCC) presented similar degrees of impairment. Antipyrine clearance was positively correlated with serum albumin (r²= 0.10, P= 0.01) and prothrombin time (r²= 0.129, P < 0.01) in all groups, except those with liver metastases. In patients with CAH, the presence of fibrosis/cirrhosis is associated with impaired antipyrine metabolism. The lack of impairment in groups with liver metastases suggests that the functional hepatic reserve is maintained even in the presence of massive neoplastic invasion.     

Hepatic metabolic ability during anasthesia Evaluation of antipyrine half-lives and their relation to enflurane metabolism

The antipyrine (phenazone) half-life was determined in 20 surgical patients to discover whether there are changes in hepatic metabolic rate during or immediately after anaesthesia compared with the pre-anaesthetic rate. Nine patients received enflurane (mean duration 8.6, SD 2.0 hours) and six patients had a balanced anaesthetic without enflurane (duration 4.4, SD 3.3 hours). A further five patients received a spinal anaesthetic with bupivacaine. The changes in antipyrine half-life were inconsistent, and there was no evidence of competitive metabolic inhibition by general anaesthesia. Antipyrine half-lives did not correlate with serum fluoride levels or urinary fluoride excretion in the case of enflurane. The mean serum inorganic fluoride concentration rose to 29 mumol/litre, and two patients had potentially nephrotoxic concentrations (64 and 50 mumol/litre) after 8 hours of exposure to enflurane though without any evident harmful effects.     

Differential induction of antipyrine metabolism by rifampicin

Summary Antipyrine is oxidised to three main metabolites in man. There is evidence that the different metabolites are products of different forms of cytochrome P-450. The effect of rifampicin administration for two weeks on the rates of formation of these metabolites was investigated in healthy volunteers. Rifampicin increased antipyrine clearance and shortened its half-life. Two weeks after stopping rifampicin the induction had largely been reversed. Clearance to all three metabolites was increased by rifampicin. Clearance to 3-hydroxymethylantipyrine was increased from 7.8±0.9 ml/min to 13.3±1.3 ml/min, to norphenazone from 5.8±0.6 ml/min to 19.3±2.1 ml/min and to 4-hydroxyantipyrine from 14.3±2.2 ml/min to 21.9±3.9 ml/min. Thus clearance to norphenazone was increased to a much greater extent than to either of the other two metabolites. It is concluded that this provides evidence for the involvement of at least two different forms of cytochrome P-450 in antipyrine metabolism in man.     

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

Pharmaceutical Research -     

Non-alcoholic steatohepatitis: Impaired antipyrine metabolism and hypertriglyceridaemia may be clues to its pathogenesis

Non-alcoholic steatohepatitis resembles alcoholic liver disease in hepatic morphology but appears to have a different natural history. We sought to assess the nature of non-alcoholic steatohepatitis by a prospective study of its clinical progression and the relationship of biochemical abnormalities to changes in serum lipids among 15 patients with this disorder. In addition, antipyrine clearance (Cl-AP), which reflects hepatic microsomal oxidative capacity, was measured serially. Although initial liver histology included micronodular cirrhosis in five cases and bridging fibrosis in another three, only one patient developed a hepatic complication during 1-10 years (median: 3.7) of follow up. This confirms the relatively benign nature of non-alcoholic steatohepatitis. Moreover, Cl-AP, which was below the normal range in 13 patients, did not change significantly during 10-40 months of follow up. However, compared with other chronic liver diseases, the reduced Cl-AP was disproportionately low relative to the uniformly normal serum albumin concentration and other indices of hepatic metabolic function. This is consistent with selective impairment of endoplasmic reticular drug oxidizing enzymes. Hyperlipidaemia was present in 11 patients. In three of these, diet-induced correction of serum triglyceride elevation was associated with reduction of hepatocellular damage as indicated by serum enzyme levels. A hypothesis that unites these and earlier findings is that release of cytokines may occur in non-alcoholic steatohepatitis and produce accumulation of free fatty acids in the liver, leading to focal necro-inflammatory lesions and the destruction or down-regulation of cytochrome P450.