Antipyrine elimination test as a guideline for selecting patients for transhepatic biliary drainage

Antipyrine elimination halflife (AP t1/2) was studied in 18 patients with obstructive jaundice along with routine liver function tests 24-48 h before the expected time of percutaneous transhepatic biliary drainage (PTBD). To see if it is possible to predict the outcome of PTBD, various predrainage parameters were correlated with the postdrainage bilirubin clearance after 1 week of drainage. Predrainage AP t1/2 correlated best with bilirubin clearance (r = 0.775, P less than 0.01) compared with predrainage serum bilirubin, alkaline phosphatase and serum proteins/albumin. Eight patients had AP t1/2 less than 15 h, while 10 had AP t1/2 greater than 15 h. Patients with AP t1/2 less than 15 h had significantly faster recovery after PTBD than patients with AP t1/2 greater than 15 h. If PTBD can be restricted to those with AP t1/2 less than 15 h, the advantages of preliminary PTBD can be achieved with minimum complications. Thus, estimation of AP t1/2 may aid in the selection of patients with obstructive jaundice who are likely to benefit by preliminary biliary decompression.     

Model-derived assessment of urea appearance in response to alanine infusion: A quantitative measure of liver function in cirrhosis

A three compartment mathematical model was used to analyse the urea response to an alanine infusion in six control subjects, and in 15 patients with liver cirrhosis and variable degree of hepatocellular failure. Model-derived coefficients were used to calculate two parameters (Y_max and T_max), able to describe the theoretical response of the conversion of amino acid derived nitrogen into urea, in response to a unit impulse in alanine concentration. They correspond to the maximum rate of conversion of nitrogen from an intermediary pool into urea and to the time delay between the impulse and Y_max, respectively. In cirrhosis, the apparent volume of distribution of infused alanine was smaller than in controls, while the conversion of alanine nitrogen into an intermediary pool of nitrogen and finally into urea nitrogen were both reduced. Also Y_max was reduced by 50% in cirrhosis, whereas T_max was increased by 50%, and both significantly correlated with galactose elimination capacity (GEC; R²= 0.706 and R²= 0.505, respectively) and with antipyrine clearance (Ap Cl; R²= 0.823 and R²= 0.576, respectively). Model-derived assessment of urea appearance in response to alanine infusion is able to quantify the functional liver cell mass, and may prove useful for the study of nitrogen metabolism in cirrhosis, mainly in relation to encephalopathy.     

Use of parallel erlang density functions to analyze first-pass pulmonary uptake of multiple indicators in dogs

The gamma and Erlang density functions describe a large class of lagged, right-skewed distributions. The Erlang distribution has been shown to be the analytic solution for a chain of compartments with identical rate constants. This relationship makes it useful for the analysis of first-pass pulmonary drug uptake data following intravenous bolus administration and the incorporation of this analysis into an overall systemic drug disposition model. However, others have shown that one Erlang density function characterizes the residence time distribution of solutes in single tissues with significant systematic error. We propose a model of two Erlang density functions in parallel that does characterize well the arterial appearance of indocyanine green, antipyrine, and alfentanil administered simultaneously by right atrial bolus injection. We derive the equations that permit calculation of the higher order moments of a system consisting of two parallel Erlang density functions and use the results of these calculations from the data for all three indicators to estimate pulmonary capillary blood volume and mean transit time in the dog. Supported in part by the National Institute of General Medical Sciences RO1-GM-43776, RO1-GM-47502, and PO1-GM-47819.     

Endotoxin depresses hepatic cytochrome P450-mediated drug metabolism in women

Aims In men, the inflammatory response to intravenous endotoxin depresses apparent oral clearances of antipyrine, hexobarbitone, and theophylline. The aim of this study was to investigate whether there might be gender differences in the regulation of hepatic cytochromes P450.
Methods Experiments were carried out in seven healthy women volunteers (ages 19–51, median 22 years). Each woman received a cocktail of the three drugs on two occassions, once after a saline injection and again after endotoxin.
Results Endotoxin injections, but not saline, caused the expected physiologic responses of inflammation including fever and increases in circulating tumor necrosis factor-α, interleukin-6, and C-reactive protein. When compared with the saline control studies, endotoxin significantly decreased clearances of all probes: antipyrine, 31% (95%CI 21%–41%); hexobarbitone, 20% (95%CI 10–31%); and theophylline, 20% (95%CI 10%–30%). The decreases were comparable with those found in the men previously studied (35%, 27%, and 22%, respectively).
Conclusions These data show that endotoxin-induced inflammation decreases hepatic cytochrome P450-mediated metabolism of selected probe drugs in women as it does in men.     

Influence of acetaminophen on antipyrine kinetics in rats

Studies have suggested that acetaminophen may inhibit the liver metabolism of several drugs. Due to the expected clinical relevance of these findings, the present study was undertaken to examine acetaminophen effects on in vivo drug metabolism in the rat, using the model substrate antipyrine. Oral doses of 15 mg/kg acetaminophen were administered twice daily for 7 days. Antipyrine kinetics were determined before and immediately after acetaminophen treatment in rats (used as their own control). Acetaminophen treatment significantly increased antipyrine half-life by 29% and reduced its clearance by 24%, without affecting its volume of distribution. Further studies are warranted to determine the relevance and mechanism of these findings.     

Hepatic blood flow and drug metabolism in patients on enzyme-inducing anticonvulsants

Summary Liver blood flow and indices of hepatic drug metabolism (antipyrine elimination rate and cytochrome P-450 concentration in liver biopsy specimens) were studied in 19 epileptics on long-term anticonvulsant treatment, and in 18 controls. The size of the liver and the total estimated liver blood flow were greater in the epileptics than in the controls, whereas the relative liver blood flow (per unit weight of the liver) was not significantly different. The epileptics had higher cytochrome P-450 levels and they eliminated antipyrine faster than the controls. It was concluded that long-term ingestion of enzyme-inducing anticonvulsants is associated with an increase in the total hepatic blood flow in parallel with the increase in liver size, and not as an independent phenomenon. Since the relative perfusion rate of the hepatocytes was unchanged, the enhanced activity of drug metabolizing enzymes is presumed to be mainly responsible for the increased drug clearance observed in epileptic subjects.     

Maternal–fetal transport kinetics of carboplatin in the perfused human placental lobule: In vitro study

Objective. Platinum-containing drugs are widely used in the treatment of various malignancies in humans. There is a paucity of data on maternal–fetal transport characteristics of one such widely used drug, carboplatin, and this prompted us to study its permeation characteristics in the human placenta in vitro.

Methods. Placentae from uncomplicated, normal pregnancies were collected postpartum. Carboplatin, along with antipyrine as internal reference marker were injected as a single bolus (100 ul) into the maternal arterial circulation of isolated perfused placental lobules and perfusate samples collected from both maternal and fetal circulations over a period of 5 minutes. National Culture and Tissue Collection medium, diluted with Earle's buffered salt solution was used as the perfusate. Carboplatin concentration in various samples was determined by atomic absorption spectrophotometry, while antipyrine concentration was assayed by spectrophotometry. Transport and pharmacokinetic data of study and reference substances were computed using appropriate parameters.

Results. The differential transport rate of carboplatin for 10, 25, 50, 75, and 90% efflux fractions in fetal venous effluent averaged 0.60, 1.35, 2.52, 3.72, and 4.49 minutes in 12 perfusions, representing 1.16 ± 0.10, 1.06 ± 0.06, 1.00 ± 0.02, 0.98 ± 0.01, and 0.99 ± 0.01, respectively, times the antipyrine reference value. Student's t-test did not show any significant difference (p > 0.05) between the control and study group data. The transport fraction (TF) of carboplatin, expressed as the fraction of the drug appearing in the fetal vein during a study period of 5 minutes, averaged 9.00 ± 0.52% of bolus dose, while antipyrine TF averaged 68.60 ± 2.01% of injected bolus dose, representing 13.1% of reference marker value. Student's t-test showed carboplatin and reference marker TF values to be significantly different (p < 0.05). Pharmacokinetic parameters such as area under the curve, clearance, time for maximum response, and absorption and elimination rates of study and reference substances showed varying differences.

Conclusions. We report for the first time that carboplatin transport from the maternal to the fetal circulation is relatively small in the human placenta at term. It is reasonable to assume that the risk for the neonate from carboplatin use in pregnancy is minimal when used in emergency clinical situations.     

Urine Antipyrine Metabolites in Rats with Different Resistance to Hypoxia Subjected to Cold Stress

We studied antipyrine metabolism in rats with different resistance to hypoxia during adaptation to cold stress. Changes in the concentrations of some antipyrine metabolites at low temperature were associated with individual resistance to hypoxia. In low-resistant rats, antipyrine metabolism was suppressed from day 5 of cold exposure to day 3 of the recovery period. In highly resistant rats, antipyrine metabolism was inhibited on day 3 of cold exposure, but returned to normal on day 3 of the recovery period.     

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.