Effect of age and liver cirrhosis on the pharmacokinetics of nitrazepam

1 The effect of age and liver cirrhosis on the pharmacokinetics of i.v. administered nitrazepam was studied in nine healthy relatively young subjects (age 22-49 years), eight healthy elderly (age 67-76 years) and 12 patients with alcoholic liver cirrhosis (age 39-66 years).

2 The elimination half-life of nitrazepam in the elderly subjects was longer than in the young ones but the difference did not reach statistical significance. Mean values (ranges) were 38 (26-64) h and 26 (19-31) h respectively.

3 The increase in elimination half-life was primarily due to an increase in volume of distribution, mean values (ranges) being 2.93 (1.96-5.33) l/kg and 1.89 (1.44-2.23) l/kg in the elderly and young groups respectively (P < 0.05).

4 The protein unbound fraction of nitrazepam tended to be higher in the elderly subjects, although the difference between the two age groups was not significant: 13.9 (11.5-15.4)% and 13.0 (11.0-15.9)% in elderly and young respectively.

5 Age had no effect on the clearance of total nitrazepam nor on the clearance of unbound nitrazepam (intrinsic clearance). Mean values (ranges) were 63 (50-87) ml/min and 489 (377-635) ml/min in the young and 64 (47-91) ml/min and 456 (348-652) ml/min in the elderly subjects respectively.

6 There were no significant differences in elimination half life, clearance and volume of distribution between patients with alcoholic liver cirrhosis and the total of healthy subjects of both age groups, mean values (ranges) being 31 (21-55) h, 59 (26-85) ml/min and 2.17 (1.57-3.22) l/kg respectively in patients and 31 (19-64) h, 63 (47-91) ml/min and 2.38 (1.44-5.33) l/kg in healthy subjects.

7 The protein unbound fraction of nitrazepam was substantially higher in the patient group: 18.9 (14.8-30.3)% as compared to 13.8 (11.0-15.9)% in the healthy subjects (P < 0.001).

8 Clearance calculated relative to unbound nitrazepam (intrinsic clearance) was significantly lower in the patient group: 320 (163-482) ml/min as compared to healthy subjects, 472 (348-652) ml/min (P < 0.001).

9 The results of this study indicate that nitrazepam action following single dose administration may be more persistent in elderly than in young people; however, steady state levels of total and unbound nitrazepam during nightly intake of the drug will not be affected by age. On the other hand, steady state levels of unbound nitrazepam in patients with liver cirrhosis will generally be about 35% higher than in healthy subjects.

     

The effect of liver cirrhosis on the pharmacokinetics of phenprocoumon

Summary Phenprocoumon was given orally to 9 patients with biopsy proven liver cirrhosis (dose range 0.12–0.25 mg/kg) and to 7 healthy volunteers (0.23 mg/kg). Concentrations of phenprocoumon were determined using HPLC in plasma and urine samples obtained for 6–7 days after drug administration. The binding of [³H]-phenprocoumon in plasma from all subjects was determined by equilibrium dialysis. Antipyrine plasma concentrations were determined spectrophotometrically following oral administration of antipyrine (1200 mg). The total body clearance of phenprocoumon was higher in the cirrhotic patients (1.64±0.16 ml/h/kg mean ± SEM) than in the healthy volunteers (0.90±0.07 ml/h/kg), however the free drug clearance was not significantly different in the patients (144±14 ml/h/kg) compared with normal (113±11 ml/h/kg). In contrast the clearance of antipyrine was much reduced in the cirrhotic group (17.5±2.9 ml/h/kg) compared with normal (35.6±3.9 ml/h/kg). The metabolic clearance of phenprocoumon via glucuronidation, is relatively unaffected during cirrhosis compared with antipyrine clearance via oxidation.     

Quinidine disposition in relation to antipyrine elimination and debrisoquine phenotype in alcoholic patients with and without cirrhosis

Single dose disposition of oral quinidine (400 mg sulfate) was studied in a control group of subjects (No. = 6) and in hospitalized alcoholic patients involving one group with (No. = 6) and one group without (No. = 11) hepatic cirrhosis. All subjects also underwent an antipyrine and a debrisoquine test. Patients with cirrhosis had a prolonged elimination half-life (29.5 +/- 5.9 h) and low clearance (24 +/- 7 ml.kg-1.h-1) of antipyrine and also a considerably higher debrisoquine metabolic ratio (18.8 +/- 3.3) than the controls, whereas the alcoholics without cirrhosis had metabolic patterns for these two test compounds comparable to those seen in the controls (antipyrine half-life: 8.8 +/- 1.1 h and 9.8 +/- 2.0 h; debrisoquine metabolic ratio: 3.6 +/- 0.7 and 3.8 +/- 1.2 for alcoholics and controls respectively). In patients with cirrhosis the apparent elimination half-life of quinidine was longer (12.8 +/- 1.8 h) whereas after oral administration clearance of quinidine (15.6 +/- 3.5 l.h-1) and quinidine/3-hydroxyquinidine ratio (9.9 +/- 2.1) were not different from controls (quinidine clearance: 13.45 +/- 1.9 l.h-1; quinidine/3-hydroxyquinidine: 10.3 +/- 2.7). A possible change in distribution patterns of quinidine in cirrhotics may explain these findings.     

Influence of hepatic cirrhosis and end-stage renal disease on pharmacokinetics and pharmacodynamics of furosemide

Summary After rapid intravenous injection of furosemide 40 mg (Fu), plasma levels were determined in 7 healthy volunteers, 8 patients with liver cirrhosis with ascites and 7 patients with end-stage renal disease (ESRD). The diuretic response was evaluated by measuring the urinary excretion of sodium and potassium and the urine volume. The mean elimination half life (tF_1/2+) of Fu averaged 51±7.7 (±SD) min in healthy subjects, 52±7.7 min in cirrhosis and 200±57 min in ESRD. The non-renal clearance (Cl_nr) in healthy subjects (56±28 ml/min) corresponds to the total plasma clearance in functionally anephric patients (54±18 ml/min). In cirrhosis there was no significant change in the disposition parameters of Fu in comparison to the healthy volunteers, but there was a significant reduction in urine sodium and volume, whereas potassium excretion remained unchanged. Fu “excretion rate — response” curves showed diminished tubular sensitivity to Fu in cirrhosis. Preliminary results were reported at the 86th Annual Meeting of the Deutsche Gesellschaft für Innere Medizin     

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.     

Lack of effect of zinc supplementation on antipyrine clearance in alcoholic liver disease

Methods: The effect of zinc supplementation on antipyrine clearance was evaluated in 14 outpatients with stable alcoholic liver disease, of whom nine had biopsy proven alcoholic cirrhosis. Results: There was no change in antipyrine clearance after 14 days of zinc supplementation (median 12.5 vs 12.9 ml · min^–1). However, a significant increase in P-prothrombin-proconvertin was found. There was a positive correlation between S-zinc and antipyrine clearance at inclusion (r_s=0.76) as well as after zinc supplementation (r_s=0.72). Conclusion: No effect of zinc supplementation on antipyrine clearance was found. The positive correlation between S-zinc and antipyrine clearance could be due to the confounding effect of alcoholic liver disease.     

Pharmacokinetics of diclofenac sodium in chronic active hepatitis and alcoholic cirrhosis

The objective of this study was to assess the pharmacokinetics of diclofenac sodium and its five metabolites following administration of a 150 mg oral dose to healthy subjects and patients with either chronic active hepatitis of varying morphology or alcoholic cirrhosis. Six healthy subjects, 6 chronic active hepatitis patients, and 6 alcoholic cirrhosis patients were enrolled in this prospective, open-label, parallel study. Blood samples were drawn at 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 312, and 480 hours, and urine samples were collected for 144 hours after administration of a single oral dose of diclofenac sodium. The mean area under the serum concentration-time curve extrapolated to infinity, oral clearance, half-life, maximal concentration, and time to peak concentration for diclofenac and its metabolites were determined and compared using analysis of variance. Cirrhotics had a mean +/- SD diclofenac AUC value (19,114 +/- 6806 ng.h/ml) significantly different (p < 0.02) from hepatitis patients (6071 +/- 1867 ng.h/ml) and healthy subjects (7008 +/- 2006 ng.h/ml), whereas healthy subjects and hepatitis patients had similar values. Comparable results were found for 4'-hydroxydiclofenac. The AUC values for 3'-hydroxydiclofenac and 3'-hydroxy-4'methoxydiclofeanc were significantly different when healthy subjects were compared to cirrhotics. However, hepatitis subjects were not significantly different from either group. The results indicate that hepatitis does not alter the pharmacokinetics of diclofenac. Alcoholic cirrhosis increased the mean diclofenac AUC approximately three times compared to normal subjects, indicating that one-third of the usual dose in cirrhotics would produce equivalent AUC values in normal subjects and subjects with alcoholic cirrhosis. However, since pharmacodynamic measurements were not made and no increase in untoward or side effects was noted in the alcoholic cirrhosis patients after a single dose, maintenance doses should be titrated to patients response.     

Altered disposition and availability of cimetidine in liver cirrhotic patients.

1 The pharmacokinetics and bioavailability of cimetidine were studied after 200 mg oral and intravenous doses in 14 patients with liver cirrhosis, and results were compared to a control group of 12 ulcer patients. 2 In cirrhotic patients, the volume of the central compartment (0.41 +/- 0.06 v 0.19 +/- 0.09 1/kg) and the volume of distribution at steady-state (1.02 +/- 0.17 v 0.80 +/- 0.24 1/kg) were significantly increased. No differences were observed in the area volume of distribution, the total systemic plasma clearance and renal clearance. The non-renal clearance was significantly decreased from 191 +/- 46 to 123 +/- 102 ml/min. 3 The bioavailability of cimetidine (area method) was significantly increased from 60 +/- 23% to 77 /+- 18% in the cirrhotic patients. Also increased was the time during which plasma levels exceeded 0.5 microgram/ml. 4 Urinary excretion of cimetidine was increased in liver cirrhosis by 32% after intravenous and by 36% after oral administration, while the amount of the sulphoxide metabolite decreased accordingly. Creatinine clearance in the cirrhotic patients was highly correlated with the renal clearance of cimetidine as well as its total plasma clearance.     

Pharmacokinetics of molsidomine and its active metabolite, linsidomine, in patients with liver cirrhosis.

The pharmacokinetics of molsidomine were investigated in six healthy volunteers and in seven patients with alcoholic cirrhosis. After a 2 mg oral dose, molsidomine elimination half-life was prolonged in cirrhotic patients (13.1 +/- 10.0 h vs 1.2 +/- 0.2 h, P less than 0.01) because of a decrease in its apparent plasma clearance (CL/F) (39.8 +/- 31.9 ml h-1 kg-1 in patients with cirrhosis vs 590 +/- 73 ml h-1 kg-1 in volunteers). The elimination half-life of the active metabolite, linsidomine (SIN-1) was also prolonged in cirrhotic patients (7.5 +/- 5.4 h vs 1.0 +/- 0.19 h, P less than 0.05). The AUC values of both molsidomine and linsidomine were increased in the cirrhotic group, but the increase in the former was considerably greater than in the latter as shown by the significant decrease of the ratio AUClinsidomine/AUCmolsidomine x 100 (4.5 +/- 6.1 in cirrhotic patients vs 23.5 +/- 3.4 in healthy volunteers, P less than 0.001). These results suggest that liver cirrhosis profoundly alters the pharmacokinetics and metabolism of molsidomine.     

The short term effects of propranolol, atenolol and labetalol on antipyrine kinetics in normal subjects.

1 The effects of three day courses of propranolol 40 mg three times daily, atenolol 100 mg twice daily and labetalol 100 mg three times daily on antipyrine kinetics were examined in 13 normal subjects. 2 The mean antipyrine clearance initially was 41.3 +/- 12.4 ml/min (mean +/- s.d.) and fell to 35.0 +/- 12.1 ml/min following propranolol (P less than 0.025), 34.5 +/- 9.5 ml/min following atenolol (P less than 0.01), and 35.2 +/- 8.6 ml/min following labetalol (P less than 0.05). 3 The prolongation in antipyrine half-life was significant only following atenolol. Propranolol only caused a significant reduction in the volume of distribution of antipyrine. 4 These adrenoceptor antagonists appear to decrease antipyrine clearance in normal subjects. The reduction in antipyrine clearance was similar with all three drugs and appeared to be independent of the differing lipid solubilities and pharmacological profiles of the adrenoceptor antagonists examined.     

Binding and disposition of sulfisoxazole in alcoholic cirrhosis

The disposition of sulfisoxazole was studied in six male patients hospitalized with biopsy-proven Laennec's alcoholic cirrhosis and six normal, healthy volunteers. Four of the patients were restudied at a time their liver disease had improved clinically. On the average, compared to the normal group, the metabolism of sulfisoxazole (clearance values with respect to unbound concentration values) appears to be unaltered for the cirrhotic patients. For patients with alcoholic cirrhosis having normal renal function for age and weight, the renal elimination of sulfisoxazole was normal. For those subjects with decreased renal function, the renal clearance of sulfisoxazole appeared to be disproportionately decreased, as evidenced by a lower-than-normal sulfisoxazole renal clearance-to-creatinine clearance values. The apparent steady-state volume of distribution of unbound sulfisoxazole was not altered in cirrhotic patients when compared to normal subjects, while the apparent volume of distribution of total drug increased by more than what could be expected from protein binding changes alone. The elimination rate constant did not differ from values found in normals. These data suggest that the total binding capacity of sulfisoxazole in cirrhotic patients is not different from that of normal subjects.     

Antipyrine pharmacokinetics in women receiving conjugated estrogens

The pharmacokinetics of a single 1.0 to 1.2-g intravenous dose of antipyrine was studied in 22 healthy female volunteers aged 28 to 70 years (mean, 45 years). Eleven subjects had been taking a conjugated estrogen preparation for at least 3 months; the other 11 subjects who were not taking conjugated estrogens and who were matched for age, weight, and smoking patterns, served as a control group. Plasma antipyrine concentrations were determined by high-pressure liquid chromatography (HPLC) in multiple plasma samples drawn 24 to 48 hours after dosage. Mean +/- SE pharmacokinetic variables in control and conjugated-estrogen groups were volume of distribution, 0.57 +/- 0.02 versus 0.56 +/- 0.02 L/kg; elimination half-life, 11.0 +/- 0.82 versus 12.6 +/- 0.89 hours; and clearance, 0.63 +/- 0.06 versus 0.54 +/- 0.03 mL/min/kg. None of the differences was significant. Although antipyrine clearance is significantly impaired by oral contraceptives, there is no evidence of altered antipyrine pharmacokinetics from treatment with conjugated estrogens.     

The effect of hepatic disease on the disposition of moricizine in humans

The pharmacokinetics of moricizine and two of its metabolites, moricizine sulfoxide and phenothiazine-2-carbamic acid ethyl ester sulfoxide, were studied in healthy control subjects and in patients with chronic liver disease (cirrhosis). Moricizine disposition was significantly altered by hepatic cirrhosis. Compared to healthy subjects, the hepatic disease patients had an increased C_max (59%), an increased t_1/2 (141%), and a reduced plasma clearance (71%). Additionally, small but statistically significant increases were observed for t_max and the fraction of moricizine not bound to plasma proteins in patients with hepatic disease. The elimination of both moricizine metabolites was also altered by hepatic dysfunction as indicated by significantly prolonged terminal half-lives. Furthermore, there was a reduction in the conversion of moricizine to moricizine sulfoxide. Both hepatic blood flow and hepatic metabolizing capacity were assessed in all subjects and patients by administration of indocyanine green and antipyrine, respectively. Indocyanine green and antipyrine plasma clearances were decreased by 38 and 51%, respectively, indicating that both functions were diminished by hepatic cirrhosis. We conclude that the moricizine dose required for arrhythmia patients with hepatic disease should be lower, and perhaps, the dosing frequency should be less than in patients with normal liver function.     

The relationship between liver volume, antipyrine clearance and indocyanine green clearance before and after phenobarbitone administration in man.

Liver volume and the clearances of antipyrine and indocyanine green have been measured before and after administration of phenobarbitone (180 mg/day) for 3 weeks to ten healthy subjects. The measurement of liver volume by an ultrasound scanning technique yielded reproducible results which were consistent with predictions of liver size by allometric methods. Before phenobarbitone, antipyrine clearance correlated with liver volume, but there was no correlation between indocyanine green clearance and liver volume. Phenobarbitone administration increased the clearance of antipyrine significantly by 90 +/- 14% but there was no significant change in indocyanine green clearance or liver volume. After phenobarbitone the correlation between antipyrine clearance and liver volume persisted. There was no correlation between indocyanine green clearance and liver volume. These results suggest that in non-medicated subjects some of the difference in antipyrine clearance is due to difference in functional hepatic parenchymal mass and that phenobarbitone increases the drug metabolising capacity per unit of hepatic mass but not total liver size.     

Antipyrine and lidocaine are cleared faster in horses than in humans: acetaminophen may be handled similarly

The following studies were designed to evaluate plasma elimination kinetics of intravenously administered antipyrine, acetaminophen and lidocaine among 9 healthy adult horses and 9 healthy drug-free humans (3 each per drug group), in order to compare potential species differences in drug-metabolizing ability. Acetaminophen is largely biotransformed in humans by hepatic glucuronide and sulfate conjugation, whereas both antipyrine and lidocaine are oxidized by hepatic microsomal mixed-function oxidases. Thus, plasma clearances of these drugs are thought to reflect differences in hepatic oxidative and conjugative activity, and possibly hepatic blood flow in the case of lidocaine. Results showed that mean (+/- SD, n = 3) acetaminophen clearance was similar in both horses (4.84 +/- 0.637 ml/min/kg) and humans (4.68 +/- 0.691 ml/min/kg). However, antipyrine clearance was 10 times greater in horses (5.83 +/- 2.21 ml/min/kg) than in humans (0.536 +/- 0.110 ml/min/kg), which may reflect enhanced hepatic microsomal activity in horses. Although lidocaine clearance in humans was similar to estimated hepatic blood flow (20.6 +/- 5.81 ml/min/kg), clearance in horses was more than 2 times greater (52.0 +/- 11.7 ml/min/kg). The cause of the higher clearance of lidocaine in horses (like dogs) remains unexplained, and may involve significant metabolism of lidocaine at extrahepatic, extravascular sites, for intravascular degradation and renal excretion of intact lidocaine in horses was negligible. Although precise biochemical mechanisms underlying pharmacokinetic parameters for these drugs in horses were not determined, it is nonetheless concluded from antipyrine results that horses may have an enhanced ability (compared with humans) to clear drugs from the circulation that are primarily metabolized in the liver by phase I oxidative reactions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Simplified approaches to the determination of antipyrine pharmacokinetic parameters.

1. The pharmacokinetics of single intravenous doses of antipyrine were determined in 96 volunteers using multiple (12 or more) plasma antipyrine concentrations measured by high-pressure liquid chromatography during 24-48 h after dosage. These kinetic estimates were compared with those based on: A, the 4 h and 12 h points only; B, the 4 h through 12 h points; C, the 8 h and 24 h points only. 2. Mean clearance values for the complete study (48.0 ml min-1) were nearly identical to abbreviated approaches A, B, and C (49.1, 49.3, and 46.4 ml min-1), and were highly correlated (r = 0.99). 3. Coefficients of variation (CV) between individual clearance values for complete vs abbreviated studies averaged 5.5%, 5.8% and 2.9%, and CVs were less than 15% in 95.8%, 93.7% and 98.9% of subjects, respectively, for methods A, B, and C. 4. Overall mean values of elimination half-life (11.9, 12.1, 12.0 and 12.5 h) and volume of distribution (43.7, 45.1, 45.2, and 44.71) were likewise very similar for complete A, B and C analyses respectively. 5. The best correlation with the complete study was observed for the 8 and 24 h sampling scheme, for which clearance values were within 5% of the reference method in 84% of subjects, and within 10% in 97% of subjects. 6. Antipyrine pharmacokinetic parameters can be estimated with reasonable precision using a simplified two-point blood sampling procedure following a single intravenous dose. Estimates of elimination half-life, volume of distribution and clearance based on 8 h and 24 h data points correlated best with complete pharmacokinetic studies.     

Pharmacokinetics of chlormethiazole in healthy volunteers and patients with cirrhosis of the liver

Summary The pharmacokinetics of chlormethiazole after oral and intravenous administration was studied in six healthy volunteers and eight patients with alcoholic cirrhosis of the liver. Plasma concentration-time curve after the intravenous infusion could adequately be described by two- or three-compartment open models both in healthy volunteers and in the patients. Based on the areas under the plasma concentration-time curves, the systemic bioavailability of oral chlormethiazole was about ten times greater in the patients than in healthy controls. The elimination of chlormethiazole was relatively less retarded in the patients, as indicated by a decrease of about 30% in its plasma clearance. In the patients the plasma protein binding of chlormethiazole was decreased, but the volume of distribution and half-life of elimination were unchanged. The increase in bioavailability of chlormethiazole was associated with significant alteration in the serum levels of bilirubin, albumin, alkaline phosphatase, prothrombin-proconvertin activity (P + P) and elimination rate of antipyrine or¹⁴C-aminopyrine. The increased bioavailability of oral chlormethiazole was due to impaired first-pass metabolism in the cirrhotic liver. A considerable reduction in dose seems to be indicated if oral chlormethiazole is used in patients with advanced cirrhosis of the liver. A substantial fraction of dose, averaging 15%, was lost during the intravenous infusion, presumably due to adsorption to the infusion tubing.     

Pharmacokinetics of famotidine in normal subjects and in patients with chronic liver disease

The pharmacokinetics of famotidine were studied in seven healthy control subjects and in 14 patients with cirrhosis, following single oral and intravenous 20-mg dose administration, and after seven daily doses of 40 mg. Following intravenous (i.v.) administration, the mean (range) total plasma clearance values were not significantly different in the patients with compensated cirrhosis (n = 7), 337 (241-576) ml/min or in the patients with decompensated cirrhosis (n = 7), 270 (120-408) ml/min compared with the control group, 370 (154-612) ml/min. The mean half-life in the compensated cirrhotics, 2.86 (1.87-4.98) h, was similar to that in the control group 2.91 (1.86-6.03) h, but it was insignificantly prolonged in the decompensated cirrhotics 3.35 (2.00-5.77) h. The mean, maximum, plasma famotidine concentrations after single oral doses were comparable between the groups but there was considerable inter-subject variability, with individual values ranging from 17 to 139 ng/ml. Peak plasma concentrations were reached within 2-3 h, although more variability was observed among patients with decompensated cirrhosis. The mean systemic availability of the drug, estimated from urinary recovery, was 0.39 (0.15-0.64) in the healthy controls, 0.35 (0.14-0.51) in the patients with compensated cirrhosis and 0.38 (0.13-0.77) in the patients with decompensated cirrhosis. No significant increases were observed in plasma trough famotidine concentrations following multiple oral dosing in any of the subjects, and the kinetic variables after the seventh dose were not significantly different from those following the single oral dose. No significant changes were observed in psychometric performance in control subjects or in patients between the pre-study day and day seven of the multiple oral dose phase.     

Antipyrine clearance in comparison to conventional liver function tests in hepatitis C virus patients

In this study, 15 healthy volunteers and 96 patients with hepatitis C virus, classified according to Child-Pugh into 36 Child-A, 31 Child-B and 29 Child-C, were examined. All subjects ingested 600 mg antipyrine in the form of hard gelatinous capsules after overnight fasting. One milliliter of saliva was collected at 4 and 24 h after ingestion of antipyrine and analyzed using high-performance liquid chromatography. Blood samples were collected from all subjects for examination, using conventional liver function tests. The pharmacokinetic variables for antipyrine were determined using the two concentration time points selected. A cut-off value of 0.34 ml/min/kg was used to distinguish between cirrhotic and non-cirrhotic patients. Alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase values were significantly higher with significantly lower antipyrine clearance in Child-A, B, and C patients than in normal volunteers. The total protein concentration was significantly lower in Child-B and C patients. Moreover, AST was significantly higher in Child-C patients and antipyrine clearance was lower in Child-B and C patients than in Child-A patients. Antipyrine clearance showed a significant negative correlation with Child-Pugh scores, total protein, the international normalization ratio of prothrombin time and globulin, and a positive correlation with albumin and albumin-to-globulin ratio. Unlike most of the conventional liver function tests, antipyrine clearance, which represents the intrinsic clearance capacity of the liver, measured using saliva, proved to be a sensitive marker of liver function. It was significantly impaired in the Child-Pugh group A patients with the least hepatic impairment. The international normalization ratio of prothrombin time was just as informative as antipyrine clearance in identifying minimal hepatic impairment.     

Simplified Determination of Antipyrine Clearance by Liquid Chromatography of a Microsample of Saliva or Plasma

We describe a simplified and rapid liquid chromatographic determination of antipyrine clearance (CL_AP) calculated from peak height ratios of drug/internal standard. Saliva or plasma was collected 24 hr after the oral administration of 1 g of antipyrine to the subject. A 25-µl aliquot of the sample is deproteinized with acetonitrile containing 3-nitrophenol (internal standard) and injected into a radial compression module equipped with a 10-µm, 8 mm × 10-cm C₁₈ cartridge, using a 0.025 M aqueous solution of sodium acetate and acetonitrile (88.5:11.5). The minimum measurable concentration was 0.2 µg/ml. The obtained CL_AP values in five healthy subjects and five patients with chronic liver disease coincided well (r > 0.9994) with those generated by the use of an established method. The antipyrine clearance in the healthy subjects ranged from 2.203 to 5.721 liters/hr, while in patients with chronic liver disease it was significantly (P < 0.0027) less (range, 0.544 to 1.103 liter/hr). We also determined antipyrine clearance in two of these subjects given lower doses of this drug and found that the dose has no significant impact on this parameter.