Antipyrine Disposition Research Articles

Effect of inflammation and proadifen on the disposition of antipyrine, lignocaine and propranolol in rat isolated perfused liver.

The effect of inflammation, induced in rats by injection of turpentine oil, on drug disposition has been evaluated in rat isolated perfused livers. The drugs studied were a low extraction drug, antipyrine, and two high extraction drugs, lignocaine and propranolol. Turpentine significantly increased the half-life of antipyrine and of propranolol, but not that of lignocaine. Proadifen (SKF 525A) significantly increased the half-life of all three drugs. Turpentine decreased the clearance of antipyrine significantly by about 50% and that of propranolol non-significantly by about 20%, but did not affect the clearance of lignocaine. Proadifen significantly decreased the clearance of all three drugs, but this was most pronounced for antipyrine. In both turpentine- and proadifen-treated rats a significant increase in volume of distribution of propranolol was observed. The results show that, as with proadifen, turpentine-induced inflammation affects the hepatic clearance of antipyrine in the rat isolated perfused liver. With both high extraction drugs, the effect of inflammation on their clearance was low or absent, in contrast to the effect of proadifen. This suggests that a possible effect of inflammation on intrinsic clearance is not large enough to influence the hepatic clearance of the high extraction drugs.

Disposition of Hexobarbitone and Antipyrine in DOCA-hypertensive Rats

The disposition of antipyrine and hexobarbitone, and their effects on drug metabolizing hepatic enzymes have been investigated in DOCA-hypertensive rats. Antipyrine pharmacokinetic parameters were the same in hypertensive and control animals. Hexobarbitone sleeping time was longer in hypertensive rats compared with controls, while the activity of hepatic hexobarbitone hydroxylase was the same in both groups. Hepatic aminopyrine-N-demethylase activity was elevated in hypertensive rats while aniline hydroxylase and aryl hydrocarbon hydroxylase were lower. Glucuronyl transferase was the same in both groups. The sensitivity of the central nervous system of hypertensive rats to hexobarbitone was not altered, as determined by hexobarbitone concentration in blood and in brain. The total hepatic blood flow (arterial and portal) was significantly increased. Thus it is suggested that the difference in the disposition of the two drugs is probably not due to drug metabolizing enzyme activity. It is likely that the increase in total hepatic blood flow and rapid saturation of hepatic hexobarbitone metabolizing enzymes have significant roles in the slower metabolism and increased activity of hexobarbitone in hypertensive rats as compared with control rats.

The effect of varying percentages of haemodilution with fluosol-DA or normal saline on antipyrine metabolism in the rat.

Antipyrine disposition and metabolism in conscious, unrestrained rats after 25 or 50% haemodilution with Fluosol or normal (0.9% NaCl) saline is reported. Rats received an intravenous antipyrine dose (20 mg kg-1) 0.5, 24, 48, or 72 h after haemodilution and its pharmacokinetic parameters have been compared with non-exchanged control animals. Haemodilution 25% with Fluosol initially depressed antipyrine metabolism for 24 h by decreasing the antipyrine urinary excretion rate constant and the formation rate constants of 4-hydroxyantipyrine (4-OH) and 3-hydroxymethylantipyrine (3-OHME). Metabolism was then increased for 48 and 72 h with a slight increase in all rate constants. Haemodilution 50% with Fluosol produced a similar pattern but with significant increases in the 3-OHME formation rate constant found at 48 and 72 h. Haemodilution 25% with saline reduced 4-OH formation for 48 h. Haemodilution 50% with saline significantly reduced antipyrine urinary excretion at all times. After a significant increase in the 4-OH and 3-OHME formation rate constants at 24 h following 50% haemodilution with saline, the rate constants were significantly decreased at 48 and 72 h. Haemodilution 25% with Flusol significantly reduced the antipyrine Vd at 0.5 and 72 h. After haemodilution 50% with Fluosol, the Vd alternated between values greater and less than control throughout the 72 h. Haemodilution 25 or 50% with saline had little influence on Vd.

Influence of the method of Fluosol-DA administration on antipyrine metabolism in the rat

Antipyrine disposition has been determined in the rat following administration of Fluosol-DA by an intravenous infusion without blood removal or a haemodilution procedure, and compared with data from sham haemodiluted rats (blood removed and returned) and control rats which only received antipyrine. Antipyrine total body and renal clearance and the formation clearance of two of its metabolites were affected differently at 48 h by the pretreatments. The haemodilution procedure enhanced, the sham haemodilution reduced, and the intravenous infusion had no effect on the phenobarbitone inducible cytochrome P450 isoenzyme activity.

Modeling and Simulation of Hepatic Drug Disposition Using a Physiologically Based, Multi-agent In Silico Liver

Validate a physiologically based, mechanistic, in silico liver (ISL) for studying the hepatic disposition and metabolism of antipyrine, atenolol, labetalol, diltiazem, and sucrose administered alone or in combination. Autonomous software objects representing hepatic components such as metabolic enzymes, cells, and microarchitectural details were plugged together to form a functioning liver analogue. Microarchitecture features were represented separately from drug metabolizing functions. Each ISL component interacts uniquely with mobile objects. Outflow profiles were recorded and compared to wet-lab data. A single ISL structure was selected, parameterized, and held constant for all compounds. Parameters sensitive to drug-specific physicochemical properties were tuned so that ISL outflow profiles matched in situ outflow profiles. ISL simulations were validated separately and together against in situ data and prior physiologically based pharmacokinetic (PBPK) predictions. The consequences of ISL parameter changes on outflow profiles were explored. Selected changes altered outflow profiles in ways consistent with knowledge of hepatic anatomy and physiology and drug physicochemical properties. A synthetic, agent-oriented in silico liver has been developed and successfully validated, enabling us to posit that static and dynamic ISL mechanistic details, although abstract, map realistically to hepatic mechanistic details in PBPK simulations.

Increased??Absorption??of??Digoxin from??the??Human??Jejunum Due??to??Inhibition??of??Intestinal Transporter-Mediated Efflux

The contribution of transport in the small intestine by the apically located efflux pump P-glycoprotein to variable drug absorption in humans is still poorly understood. We therefore investigated whether inhibition of intestinal P-glycoprotein-mediated efflux by quinidine leads to increased absorption of the P-glycoprotein substrate digoxin. Using a multilumen perfusion catheter, we investigated the impact of P-glycoprotein inhibition on absorption of two compounds: the P-glycoprotein substrate digoxin and the marker for passive transcellular absorption antipyrine. Two 20cm adjacent jejunal segments were isolated with the multilumen perfusion catheter in seven healthy subjects. Unlabelled and deuterated digoxin and antipyrine, respectively, were simultaneously infused into either of the intestinal segments. One of the segments was additionally perfused with the P-glycoprotein inhibitor quinidine. Intestinal perfusates were collected for 3 hours, and drug concentrations were determined in the intestinal perfusates, plasma and urine. Quinidine did not affect the disposition of antipyrine. In contrast, coadministration of quinidine into one jejunal segment caused a considerable increase in the amount of digoxin absorbed from this segment compared with the absorption from the other quinidine-free segment (22.3 +/- 8.9% vs 55.8 +/- 21.2% of the dose; p < 0.05). Accordingly, the area under the plasma concentration-time curve and the maximum plasma concentration of digoxin were considerably higher when luminal quinidine was coadministered (p < 0.05 and p < 0.001, respectively). Differences in digoxin absorption from the two intestinal segments were also reflected by pronounced differences in urinary digoxin elimination (5.5 +/- 3.3% vs 19.2 +/- 8.1% of the dose; p < 0.01). P-glycoprotein inhibition in enterocytes increases systemic exposure of orally administered drugs that are P-glycoprotein substrates. These data highlight the importance of the small intestine as an active barrier against xenobiotics.

A porcine model for fixed drug eruptions in humans: the case of antipyrine in the Yucatan micropig

To date, there is no acceptable animal model to investigate fixed drug eruptions (FDEs) in humans. We briefly report here observations suggesting that the Yucatan micropig may be a useful animal model for that purpose. During an investigation of antipyrine absorption and disposition, we observed the development of FDEs after intravenous administration of a 1 g dose. Our observations were consistent with those reported in several investigations of humans taking a single dose of antipyrine. To confirm these results, a naïve micropig was challenged. A male uncastrated Yucatan micropig (27.2 kg) was given a 1 g dose of antipyrine intravenously. After 30 days, this pig was rechallenged with the same intravenous dose of antipyrine (1 g). Blood samples were obtained to examine immunological endpoints. During the initial challenge, a fluid plaque (ca. 1-1.5 cm) appeared on the left hip of the pig ca. 6 h after dosing. After the rechallenge, inflamed pink patches were observed at the same sites where the blisters formed initially; however, no blisters re-formed. Changes of neutrophil, lymphocyte and eosinophil levels from baseline were noted 8 h after challenge. The micropig did not seem otherwise affected by the FDEs. These observations suggest that the Yucatan micropig, or swine in general, may be a useful animal model for detecting drugs that may cause FDEs in humans.

Initial antipyrine disposition in man is altered by propranolol

Purpose β-Adrenergic antagonists decrease intravenous (IV) anesthetic dose requirements. The present study determined the effect of propranolol on antipyrine (AP) disposition from the moment of rapid IV injection using a recirculatory pharmacokinetic (PK) model. AP is a physiologic marker that distributes to a volume as large as total body water in a blood flow-dependent manner and is a surrogate for many lipophilic drugs, including IV anesthetics. Methods AP disposition was determined twice in 5 healthy adult males in this IRB-approved study, once during a propranolol infusion. After rapid AP injection, arterial blood samples were collected frequently for 2 min and less frequently thereafter. Plasma AP concentrations were measured by HPLC. AP disposition was characterized, using SAAM II, by a recirculatory PK model that describes drug disposition from the moment of injection. Parameters were compared using the paired t-test. Results The disposition of concomitantly administered indocyanine green (ICG) demonstrated that propranolol decreased cardiac output (C.O.) at the expense of the fast peripheral (nonsplanchnic) intravascular circuit. AP AUC was doubled for at least the first 3 min after rapid IV injection due to both decreased C.O. and maintenance of nondistributive blood flow at the expense of a two-thirds reduction of blood flow (intercompartmental clearance) to the rapidly equilibrating (fast, splanchnic) tissue volume. Conclusion The increase in AP AUC due to the propranolol-induced alteration of initial AP disposition could explain decreased IV anesthetic dose requirements in the presence of β-adrenergic blockade. Clinical Pharmacology & Therapeutics (2004) 75, P34–P34; doi: 10.1016/j.clpt.2003.11.128

The concordance of early antipyrine and thiopental distribution kinetics.

Studies of factors affecting the initial disposition of drugs with a rapid onset of effect following i.v. administration have used antipyrine as a surrogate for lipophilic drugs because it lacks cardiovascular effects. The present study tested the assumption that antipyrine is a useful surrogate for the flow-dependent tissue distribution of the lipophilic drug thiopental by comparing the recirculatory pharmacokinetic models of antipyrine and thiopental disposition after concomitant administration to five dogs anesthetized with 1.5% halothane. The pharmacokinetics of indocyanine green, a marker of the intravascular behavior of antipyrine and thiopental, and antipyrine in these dogs was nearly identical to that described previously in dogs anesthetized with 1.5% halothane but not given thiopental. The total volume of distribution of the highly lipophilic drug thiopental was more than 60% larger than that of antipyrine, 53 versus 33 liters, respectively. Nonetheless, the initial distribution kinetics of the two drugs, including the pulmonary tissue volume and the volume of the nondistributive pathway as well as the clearance to it, were nearly identical. As a result, the fraction of cardiac output involved in distribution of the two drugs to peripheral tissues was similarly identical, although the distribution of cardiac output between clearance to the rapidly equilibrating tissues and clearance to the slowly equilibrating tissues differed slightly. This study validates the assumption that antipyrine is a useful surrogate for lipophilic drugs in pharmacokinetic studies in which physiologic stability is desirable to meet the assumption of system stationarity.

Clinical pharmacokinetics of quetiapine: an atypical antipsychotic.

Quetiapine is a dibenzothiazepine derivative that has been evaluated for management of patients with the manifestations of psychotic disorders. In pharmacokinetic studies in humans, quetiapine was rapidly absorbed after oral administration, with median time to reach maximum observed plasma concentration ranging from 1 to 2 hours. The absolute bioavailability is unknown, but the relative bioavailability from orally administered tablets compared with a solution was nearly complete. Food has minimal effects on quetiapine absorption. The drug is approximately 83% bound to serum proteins. Single and multiple dose studies have demonstrated linear pharmacokinetics in the clinical dose range (up to 375mg twice daily). The drug is eliminated with a mean terminal half-life of approximately 7 hours. The primary route of elimination is through hepatic metabolism. In vitro studies show that quetiapine is predominantly metabolised by cytochrome P450 (CYP) 3A4. After administration of [14C]quetiapine, approximately 73% of the radioactivity was excreted in the urine and 21% in faeces. Quetiapine accounted for less than 1% of the excreted radioactivity. 11 metabolites formed through hepatic oxidation have been identified. Two were found to be pharmacologically active, but they circulate in plasma at 2 to 12% of the concentration of quetiapine and are unlikely to contribute substantially to the pharmacological effects of the drug. The pharmacokinetics of quetiapine do not appear to be altered by cigarette smoking. Oral clearance declines with age, and was reduced in 2 of 8 patients with hepatic dysfunction but not in patients with renal impairment. Quetiapine has no effect on the in vitro activity of CYP1A2, 2C9, 2C19, 2D6 and 3A4 at clinically relevant concentrations. The lack of effect of quetiapine on hepatic oxidation was confirmed in vivo by the lack of effect of quetiapine on antipyrine disposition. Quetiapine had no effect on serum lithium concentration. Phenytoin and thioridazine increase the clearance of quetiapine, and ketoconazole decreases clearance. No clinically significant effects of cimetidine, haloperidol, risperidone or imipramine on the pharmacokinetics of quetiapine were noted. Quetiapine dosage adjustment, therefore, may be necessary when coadministered with phenytoin, thioridazine or other potent CYP3A4 inducers or inhibitors. The relationship between the therapeutic effects and the plasma concentrations of quetiapine has been investigated in a multicentre clinical trial. There was no statistically significant association between trough plasma quetiapine concentration and clinical response as measured by traditional assessments of psychotic symptom severity. Subsequent clinical studies of the plasma concentration versus effect relationships for quetiapine may help to further define guidelines for dosage regimen design.

Antipyrine clearance and metabolite formation in primary biliary cirrhosis.

The disposition of antipyrine is altered and may be a prognostic factor in the presence of various types of hepatic dysfunction. The object of the present study was to investigate whether antipyrine clearance and metabolite formation are useful to detect altered metabolic function in primary biliary cirrhosis. Saliva clearance of antipyrine and the formation clearance of antipyrine metabolites (hydroxymethylantipyrine, HMA; norantipyrine, NORA; and 4-hydroxyantipyrine, OHA) were investigated in a group of 34 women with biopsy-proven PBC (mean age 60 years; range 39-87 years) and in 15 healthy control women (mean age 62 years; range 46-78 years). Parameters of antipyrine clearance of patients in stage I and II were similar to those observed in healthy subjects. When compared to patients in stage I, patients in advanced stages showed a reduction in antipyrine clearance (-29% and -44% in stages III and IV, respectively) and increases in antipyrine half-life (+24% and +75% in stages III and IV, respectively). The reduction in antipyrine clearance was due to a reduction in the formation of all three antipyrine metabolites, with the formation clearance of both HMA and NORA decreasing to a slightly greater extent than that of OHA. Antipyrine clearance correlated significantly with serum bilirubin (P < 0.017) and the Mayo risk score (P < 0.001). Logistic regression analysis indicated that antipyrine clearance was an independent predictor of the histological stage of the disease (P < 0.001). Antipyrine clearance and metabolite formation is a sensitive parameter for assessing hepatic metabolic function in primary biliary cirrhosis.

Lack of effect of repeated administration of tripelennamine on antipyrine disposition in camels

Lack of effect of repeated administration of tripelennamine on antipyrine disposition in camels

Lack of effect of repeated administration of tripelennamine on antipyrine disposition in camels.

Lack of effect of repeated administration of tripelennamine on antipyrine disposition in camels.

Isoflurane alters the recirculatory pharmacokinetics of physiologic markers.

Earlier studies have demonstrated that physiologic marker blood concentrations in the first minutes after administration, when intravenous anesthetics exert their maximum effect, are determined by both cardiac output and its distribution. Given the reported vasodilating properties of isoflurane, we studied the effects of isoflurane anesthesia on marker disposition as another paradigm of altered cardiac output and regional blood flow distribution. The dispositions of markers of intravascular space and blood flow (indocyanine green), extracellular space and free water diffusion (inulin), and total body water and tissue perfusion (antipyrine) were determined in four purpose-bred coonhounds. The dogs were studied while awake and while anesthetized with 1.7%, 2.6%, and 3.5% isoflurane (1.15, 1.7, and 2.3 minimum alveolar concentration, respectively) in a randomized order determined by a Latin square experimental design. Marker dispositions were described by recirculatory pharmacokinetic models based on very frequent early, and less frequent later, arterial blood samples. These models characterize the role of cardiac output and regional blood flow distribution on drug disposition. Isoflurane caused a significant and dose-dependent decrease in cardiac output. Antipyrine disposition was profoundly affected by isoflurane anesthesia, during which nondistributive blood flow was maintained despite decreases in cardiac output, and the balance between fast and slow tissue volumes and blood flows was altered. The isoflurane-induced changes in marker disposition were different than those the authors reported previously for halothane anesthesia, volume loading, or hypovolemia. These data provide further evidence that not only cardiac output but also its peripheral distribution affect early drug concentration history after rapid intravenous administration.

Physical exercise and improvement of liver oxidative metabolism in the elderly.

Drug metabolizing capacity is generally reduced in the elderly, and physical exercise has been reported to increase drug oxidative metabolism. The purpose of this investigation was to study the effects of engagement in a program of regular physical exercise on the clearance and metabolite excretion of antipyrine, a marker of oxidative metabolism, in elderly subjects. The saliva clearance of antipyrine and the production clearances of antipyrine metabolites were studied in 37 elderly women (mean age 66 years). Subjects attended 60-min sessions three times a week for 12 weeks. Each session consisted of both aerobic (training of cardiorespiratory capacity) and nonaerobic (training of muscular strength/endurance and flexibility/coordination) exercises performed at 50-75% of maximum oxygen uptake. Antipyrine was administered orally and pharmacokinetic parameters were obtained from saliva and urine samples. After 3 months of participation in the exercise program, salivary antipyrine clearance was significantly increased by 17% mean (SEM) 0.42 (0.02) vs 0.36 (0.02) ml/min/kg; P < 0.05) and the half-life of antipyrine was significantly reduced by 18% (17.9 (1.1) vs 22.3 (1.3) h; P < 0.05). No significant change with exercise was observed in the renal clearance of antipyrine or in the norantipyrine formation clearance, but significant increases were found for hydroxymethylantipyrine [42 (5) vs 32 (4) microl/kg/min; P < 0.05; +31%] and 4-hydroxyantipyrine [243 (18) vs 194 (17) microl/kg/min; P < 0.05; +25%] formation clearances. These findings indicate that regular exercise leads to increased disposition of antipyrine in the elderly and that the main metabolic pathways of the compound are changed differentially.

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.

THE EFFECTS OF LANSOPRAZOLE ON THE DISPOSITION OF ANTIPYRINE AND INDOCYANINE GREEN IN NORMAL HUMAN SUBJECTS

This study was designed to evaluate the potential effects of acute and chronic daily oral doses of lansoprazole (60 mg) on the disposition of antipyrine, an almost completely metabolized low hepatic extraction compound, and indocyanine green, a hepatically secreted compound with high extraction ratio. The study utilized a randomized, placebo-controlled, double-blind, two-period crossover design. Sixteen of 18 subjects completed all phases of the study. Both antipyrine (10 mg kg(minus sign1)) and indocyanine green (0.5 mg kg(minus sign1)) were administered as single intravenous bolus doses on Days 1 and 7 of lansoprazole or placebo dosing. Acute exposure to lansoprazole had no statistically significant effects on the plasma pharmacokinetics of indocyanine green or antipyrine. After the seventh dose, there was a small but statistically significant reductions in indocyanine green total body clearance (CL), and elimination rate constant of 10.6% and 8%, respectively. Additionally, a small statistically significant reduction (8.6%) in antipyrine volume of distribution was detected. No other plasma antipyrine pharmacokinetic parameters were changed with concomitant lansoprazole administration. About a 12% increase in the recovery of one of the major antipyrine urine metabolites (NORA) was detected. Overall, this study demonstrates little or no effect of lansoprazole on the pharmacokinetics of antipyrine and indocyanine green.

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.

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.

Antipyrine as a Model Drug Substance to Assess Oxidative Metabolism

We read with interest the article by Crussell-Porter et al 1 on the effect of low-dose fluconazole on the effect of warfarin. We agree with the conclusion of the authors that close monitoring of prothrombin times is recommended during concomitant therapy with fluconazole. Our division demonstrated a similar effect on the pharmacokinetics of terfenadine by fluconazole. 2 We do, however, disagree with the authors' statement that the inhibitory effects of fluconazole are minimal because it does not alter the disposition of antipyrine in humans. While it is true that antipyrine has traditionally been considered a model drug for evaluating drug metabolizing capacity, 3 hepatic oxidative metabolism involves numerous P450 subfamilies, all of which do not necessarily contribute to the metabolism of antipyrine. 4 That is to say, antipyrine metabolism may be affected differently from warfarin 5 or even unaffected by well-known inhibitors of drug metabolism, 6 including ketoconazole. 7,8 For