Age-related differences in hepatic drug clearance in children: studies with lorazepam and antipyrine

The disposition of intravenous antipyrine and lorazepam, administered as model substrates for hepatic oxidative metabolism and conjugation, was evaluated in 50 children (mean age, 7.8 years; range, 2.3 to 17.8 years) with acute lymphocytic leukemia in complete remission and compared with a group of ten healthy adults. Antipyrine clearance normalized to body weight was significantly greater in children than in adults (0.91 versus 0.59 ml/min/kg; p = 0.012), but was not different when normalized to body surface area. In contrast, lorazepam total clearance (CL) and unbound clearance (CLu) normalized to body weight were not significantly different between children and adults but were smaller in children when normalized to body surface area (CL = 31.9 versus 40.6 ml/min/m2, p = 0.036; CLu = 352 versus 485 ml/min/m2, p = 0.010). The mean lorazepam fraction unbound in children was 0.087, which was not different from adult volunteers (0.084). This study has identified significant differences between children and adults in the disposition of these two compounds, with higher milliliter per minute per kilogram clearance for antipyrine but not lorazepam.     

Hepatic clearances of antipyrine, indocyanine green, and galactose in normal subjects and in patients with chronic liver diseases

Blood clearance of antipyrine, indocyanine green, and galactose were measured to evaluate the alterations of effective hepatic blood flow and hepatic intrinsic clearances in chronic liver diseases. Galactose blood clearance, which may be taken as effective hepatic blood flow, decreased by approximately 30% in patients with cirrhosis (12.49 +/- 0.76 ml/min/kg; mean +/- SE; n = 17) compared with normal subjects (18.17 +/- 1.03 ml/min/kg; n = 5). In patients with cirrhosis, intrinsic clearances of antipyrine (0.178 +/- 0.014 ml/min/kg; n = 17) and indocyanine green (6.19 +/- 1.38 ml/min/kg; n = 7) showed 61% and 85% reduction, respectively, compared with those of normal subjects (0.462 +/- 0.048 ml/min/kg; n = 5; 41.72 +/- 7.75 ml/min/kg; n = 5). Considering that indocyanine green and antipyrine are eliminated by different hepatic mechanism, these mechanisms may not be equally sensitive to decrements in hepatic function. In addition, fractional reductions of intrinsic clearances for these compounds are thus much greater than that of effective hepatic blood flow.     

Simultaneous administration of multiple model substrates to assess hepatic drug clearance

We have evaluated a method to simultaneously assess three major processes involved in hepatic drug clearance using three model substrates administered simultaneously as a 5-minute intravenous injection. Lorazepam, indocyanine green, and antipyrine are used to assess conjugation, liver blood flow, and microsomal oxidative metabolism, respectively. These substrates were administered individually and as a mixture to 10 healthy adult male volunteers to determine if clearances of any of the compounds were affected by simultaneous administration. Mean clearances of the substrates were not different when administered alone (9.97, 0.78, and 0.53 ml/min/kg) vs. together (11.5, 0.89, and 0.52 ml/min/kg), using a paired t test. Since we were using this method to assess hepatic drug clearance in children with leukemia, the effect of short-term allopurinol was assessed. The three model substrates were administered to the volunteers after 0, 1, 8, and 22 days of treatment with allopurinol, 200 mg t.i.d. There was no change in mean clearance of any of the three compounds at any point during allopurinol treatment (repeated-measures ANOVA). We conclude that this technique is a simple and valid method to simultaneously assess three major processes involved in hepatic drug clearance and is not affected by up to 22 days of oral allopurinol treatment. This simple technique, requiring a single set of blood samples, has potential applications in the assessment of developmental changes in hepatic drug clearance, as well as the effects of environmental, therapeutic, and pathophysiologic factors on three major processes involved in hepatic drug clearance.     

Ranitidine does not impair oxidative or conjugative metabolism: noninteraction with antipyrine, diazepam, and lorazepam

Potential interactions of ranitidine with antipyrine, diazepam, and lorazepam were evaluated. Ten healthy male subjects were injected intravenously with antipyrine (1.2 gm), diazepam (10 mg), or lorazepam (2 mg) on two randomly assigned occasions, once in the otherwise drug-free state and once while concurrently taking a therapeutic ranitidine dose of 150 mg every 12 hr. Kinetic analysis for antipyrine showed no change in elimination t1/2 between trials (mean, 11.6 and 11.5 hr) with no change in volume of distribution (Vd) or total clearance (0.77 and 0.75 ml/min/kg). Diazepam analysis also showed unchanged t1/2 (32.3 and 28.9 hr) with no change in Vd or total clearance (0.42 and 0.39 ml/min/kg). Lorazepam as well had unchanged t1/2 (11.7 and 11.3 hr), Vd, and total clearance (1.52 and 1.65 ml/min/kg). Therefore ranitidine, unlike cimetidine, has no effect on either human hepatic drug oxidation, as measured by antipyrine and diazepam clearance, or human drug conjugation, as measured by lorazepam clearance.     

Comparative evaluation of the effects of isradipine and diltiazem on antipyrine and indocyanine green clearances in elderly volunteers

Calcium antagonists have been shown to depress hepatic enzymes and accelerate hepatic blood flow. This study was designed to compare the effects of two calcium antagonists, isradipine and diltiazem, on antipyrine and indocyanine green (ICG) clearances in the elderly. Eighteen elderly subjects (aged 65 to 80 years) received either isradipine (5 mg every 12 hours), diltiazem (90 mg every 8 hours), or placebo (every 12 hours) for 4 days. On the third day after the study treatment, a 0.5 mg/kg dose of ICG was administered. Blood samples were obtained over 20 minutes for HPLC determination of ICG plasma concentrations. Ten minutes later, subjects ingested 1.2 gm antipyrine. Blood samples were obtained over 48 hours for HPLC determination of antipyrine plasma concentrations. Mean +/- SD antipyrine clearance after diltiazem (0.0258 +/- 0.0065 L/hr/kg) was significantly lower than that observed after isradipine (0.0334 +/- 0.0098 L/hr/kg) or placebo (0.0329 +/- 0.0082 L/hr/kg). Antipyrine clearance after isradipine was not significantly different from that after placebo. Mean +/- SD ICG clearances after diltiazem (9.17 +/- 1.35 ml/min/kg) or isradipine (9.57 +/- 1.82 ml/min/kg) were significantly higher than that observed after placebo (8.06 +/- 1.45 ml/min/kg). These findings suggest that diltiazem, but not isradipine, affects hepatic enzyme activity in the elderly. Both agents accelerate ICG clearance, a marker of hepatic blood flow.     

Food effects on propranolol systemic and oral clearance: support for a blood flow hypothesis

The influence of a high-protein meal as compared to fasting on the disposition of simultaneous intravenous and oral doses of propranolol, as well as on indocyanine green clearance, was examined in six normal subjects. The intravenous dose (0.1 mg/kg) was unlabeled propranolol and the oral dose (80 mg) was a stereospecifically deuterium-labeled pseudoracemate of propranolol. Systemic clearance of propranolol increased 38%, from 1005 +/- 57 to 1384 +/- 115 ml/min (mean +/- SE; P less than 0.05) as a result of the meal, with no change in t1/2 or apparent volume of distribution. A 12% decrease in oral clearance occurred with the meal but was not statistically significant (3717 +/- 185 ml/min, fasting; 3245 +/- 498 after meal), whereas bioavailability increased 67% (27.2% +/- 1.7% fasting; 45.5% +/- 4.3% after meal; P less than 0.01). Estimated hepatic blood flow, as measured by indocyanine green clearance, rose 34% 60 minutes after the meal (1719 +/- 155 ml/min fasting; 2304 +/- 218 ml/min after meal; P less than 0.02). A difference was observed in the oral clearance of the propranolol enantiomers in the fasting state, but this difference was unaffected by the meal. These alterations in propranolol disposition, as the result of a high-protein meal, are consistent with a transient increase in hepatic blood flow.     

The clearance of antipyrine and indocyanine green in normal subjects and in patients with chronic lever disease.

The pharmacokinetics after oral administration of 1,200 mg antipyrine and intravenous administration of 0.5 mg/kg indocyanine green have been investigated in 6 normal subjects and in 20 patients with chronic liver disease of varying etiology. Severe impairment of liver function associated with a decrease in serum albumin, elevation in serum bilirubin, or prolongation in prothrombin time correlated with a fall in the clearance of both drugs. The clearance of the two drugs correlated well in normal subjects and in patients with chronic liver disease. The presence of a surgical portacaval anastomosis was associated with a lower indocyanine green clearance for comparable clearance of antipyrine. The concept of functioning hepatic parenchymal mass is proposed as a common rate-limiting parameter for the elimination of the two drugs.     

Disposition of Misoprostol and Its Active Metabolite in Impaired Hepatic Function

The pharmacokinetics of misoprostol and its active metabolite, misoprostol acid, was assessed in 17 healthy subjects and 17 subjects with various degrees of hepatic impairment. Before misoprostol administration, subjects underwent antipyrine and indocyanine green clearance studies to assess hepatic functional capacity. Subjects were administered 400 mcg of oral misoprostol in an open-label design. There was a lower antipyrine clearance in the group with hepatic disease as compared to normal volunteers (0.56 versus 0.80 ml min(minus sign1) kg(minus sign1), respectively, p = 0.022). There was no difference in indocyanine green clearance values between groups. The C(max), t(1/2)&bgr, and [Formula: see text] tended to be larger in the hepatic group; however, there was no statistical difference. Adverse events, mostly gastrointestinal in nature, occurred more often in the subjects with hepatic disease. These data suggest the pharmacokinetics of misoprostol may be altered in the presence of hepatic disease. However, because of significant interpatient variability, definitive dosing recommendations cannot be made. Further study in this area is needed.     

Effect of experimental hemorrhagic shock on hepatic drug elimination.

OBJECTIVE: Exogenous substrates were used to measure hepatic function for the purposes of determining organ dysfunction and to evaluate the effect of experimental hemorrhagic shock with resuscitation on hepatic drug elimination. DESIGN: Prospective, controlled, non-randomized crossover trial. INTERVENTIONS: Eleven chronically instrumented immature swine were studied using a fixed-volume hemorrhage model (45 mL/kg blood removal over 15 mins) followed by resuscitation with lactated Ringer's solution at three times the volume of shed blood. One week before and immediately after hemorrhage and resuscitation, hepatic function markers (indocyanine green and antipyrine) were simultaneously administered intravenously. MEASUREMENTS: Physiologic data and blood samples were collected over 12 hrs after drug administration. Drug clearances, volumes of distribution, and half-lives were determined. MAIN RESULTS: For indocyanine green, there was no substantial change in pharmacokinetics from preshock to postshock, suggesting minimal change in hepatic blood flow. For antipyrine, clearance was decreased by 30% after shock and resuscitation (p = .05), suggesting that oxidative metabolism was acutely impaired. CONCLUSIONS: The information indicates that hepatic oxidative drug metabolism may be impaired early after hemorrhagic shock and that dosages of drugs in this class should be carefully examined when administered to patients who have sustained injury with hemorrhagic shock.     

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.     

Periportal localization of lorazepam glucuronidation in the isolated perfused rat liver

The relative effects of pretreatment with allyl alcohol and carbon tetrachloride on oxidative and glucuronide metabolism of lorazepam have been compared in the isolated perfused rat liver. Livers from rats pretreated for 24 hr with allyl alcohol (1.8 ml/kg, 1:50 solution, to induce pericentral hepatic necrosis), carbon tetrachloride (0.8 mg/kg in corn oil, to induce perivenular hepatic necrosis), or vehicle were perfused with 20% rat blood, 80% Krebs bicarbonate buffer at 20 ml/min. After 300 micrograms of lorazepam had been added to the reservoir, perfusate concentrations of lorazepam were measured in the perfusate at timed intervals. After 180 min, lorazepam and lorazepam glucuronide were measured in perfusate, bile, and liver homogenate. Allyl alcohol and carbon tetrachloride lowered lorazepam clearance by 47% and 77%, respectively. Recovery of lorazepam glucuronide after 180 min was lowered by 35% by treatment with allyl alcohol and increased 73% by treatment with carbon tetrachloride. Glucuronide recovery permitted estimation of fractional glucuronide vs. nonglucuronide clearance. In control rats, glucuronide clearance accounted for 25% of total clearance. Allyl alcohol caused a 64% reduction in glucuronide clearance but only a 39% reduction in nonglucuronide clearance. In contrast, carbon tetrachloride caused a 60% reduction in glucuronide clearance but an 83% reduction in nonglucuronide clearance. The differences in ratios of the changes in glucuronide and nonglucuronide clearance provide further circumstantial evidence that is consistent with the hypothesis of predominant periportal localization of glucuronidation and pericentral localization of oxidative metabolism of lorazepam.     

The effect of propylene glycol on antipyrine clearance in humans

To evaluate the potential interaction of propylene glycol on hepatic drug oxidation, antipyrine disposition was measured in 10 healthy subjects who received 1.2 gm antipyrine alone on one occasion and 1.2 gm antipyrine with propylene glycol on a second occasion. Propylene glycol was given as a 5 ml dose every 4 hours during the 48 hours of the study. Propylene glycol had no effect on antipyrine half life (11.7 hours control vs. 12.1 hours treatment), clearance (42.6 vs. 39.2 ml/min), or volume of distribution (42.1 vs 41.9 L). At a dose similar to that used as a vehicle for administration of other drugs, propylene glycol had no significant effect on antipyrine clearance in humans.     

The effect of ciprofloxacin on antipyrine metabolism

The effect of multiple-dose ciprofloxacin on antipyrine metabolism was studied in patients suffering from bacterial infections. The patients were given antipyrine 15 mg/kg intravenously before and after ciprofloxacin treatment. The dosage of ciprofloxacin was 500 mg bd by mouth for 8-10 days. Blood samples were taken at 0, 2, 4, 6, 10 h. Antipyrine total clearance was significantly decreased after ciprofloxacin treatment (0.85 +/- 0.45 vs. 0.52 +/- 0.24 ml/min/kg): elimination rate constants for antipyrine were decreased in all patients after ciprofloxacin, whereas no change in volume of distribution was observed. The average half-life of antipyrine was increased from 9.45 +/- 3.74 h to 14.92 +/- 3.32 h. In two males with advanced chronic hepatic failure the antipyrine half-lives were extremely prolonged. Our results support the hypothesis that ciprofloxacin inhibits intrinsic hepatic drug-metabolizing capacity and may be a source of clinically important drug interactions, particularly in patients with liver disease.     

Recovery of hepatic clearance and extraction following a release of common bile duct obstruction in the rat

The rat of recovery for hepatic clerance and extraction following release of common-duct obstruction was investigated in the rat. Male Wistar rats underwent ligation of a cannulated common bile duct. Two weeks later, the cannula was opened and implanted into the duodenum, thus re-establishing enterohepatic circulation. Hepatic extraction and indocyanine green clearance were determined in three groups of six rats each, which differed by the time elapsed from the re-establishment of communication between the common bile duct and duodenum, i.e., 1, 48 and 168 h, respectively. A fourth group, in which a sham operation was performed, served as a control. Clearance was reduced from 16.9±2.5 ml/min per kg in the control group to 2.9±0.8, 5.4±2.4, and 8.5±3.3 ml/min per kg 1, 48, and 168 h, respectively, after release of common-bile-duct obstruction. Extraction rate was reduced from 37.3±5.9% to 17.5±2.7% in the 1st hour and recovered completely at 1 week. Thus, in the rat, release of a 2-week common-bile-duct obstruction is associated with complete recovery of the extraction capacity of the liver within a week, but only incomplete recovery of clearance. This decrease in clearance seems to be due to a decrease in effective hepatic blood flow, mostly probably due to the development of porto-systemic shunts.     

Biliary excretion of organic anions in diabetic rats

Little definitive data are available concerning the effects of insulin deficiency on the hepatic uptake and biliary excretion of endogenous or xenobiotic substances. To expand our understanding of this area, male Sprague-Dawley rats were pretreated with streptozotocin (45 mg/kg i.v.) to induce uncontrolled diabetes. Four to five weeks later, diabetic rats exhibited elevations in serum glucose (640 +/- 13 mg/dl), biliary glucose (307 +/- 35 mg/dl), urine output (166 +/- 11 ml/24 hr), basal bile flow rate (73 +/- 2 microliter/min/kg), liver weight/body weight ratio and bile acid pool size. Polyphagia and generalized muscle atrophy were also evident. Plasma disappearance and biliary excretion of several organic anions were studied after i.v. administration. There were no differences between control and diabetic rats in the plasma elimination and biliary excretion of eosin, phenol-3,6-dibromphthalein disulfonate and sulfobromophthalein. Although hepatic uptake was unchanged, the biliary excretion of amaranth was decreased 30% in diabetic rats. There were no differences in bile flow rate in control or diabetic rats after administration of these four anions. In contrast, administration of indocyanine green, bromcresol green and rose bengal did not depress bile flow in diabetic rats as was observed in control rats. In addition, the rate of maximal biliary excretion was increased by 390, 240 and 151% for rose bengal, indocyanine green and bromcresol green, respectively. Plasma clearance of rose bengal was 65% higher in diabetic rats. Total body clearance and steady-state volume of distribution values for all other anions were not different after induction of diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Extrarenal sorbitol clearance after liver transplantation.

Extrarenal sorbitol clearance was measured in liver transplant patients after a steady-state perfusion. Four measurements were performed in 3 patients with various liver diseases (beginning or patent acute rejection, cytomegalovirus hepatitis, hepatic metastasis). The mean (+/- SD) extrarenal sorbitol clearance was 14.8 +/- 0.1 ml/min.kg. In 5 patients with minimal or no liver abnormalities, the mean from 5 measurements of extrarenal sorbitol clearance was 18.9 +/- 5.0 ml/min.kg. Extrarenal sorbitol clearance values in this later group were higher than the values previously reported in healthy subjects.     

Pharmacokinetics of flecainide in patients with cirrhosis of the liver

The pharmacokinetics of flecainide were studied in six patients with cirrhosis of the liver and in six healthy subjects after a single 2 mg/kg intravenous dose. Hepatic biotransformation capability before flecainide dosing was assessed by antipyrine challenge. The mean plasma antipyrine t1/2 for patients (42.2 hours) was longer (p less than 0.01) than that for subjects (11.7 hours). For control subjects, the plasma t1/2 of flecainide (9.5 hours) was shorter (p less than 0.01), plasma clearance (9.1 ml/min/kg) was faster (p less than 0.01), and volume of distribution (7.5 L/kg) was smaller (p less than 0.05) compared with corresponding values in patients. Renal clearance did not differ (p greater than 0.05) between the two groups. The mean ratio of renal clearance to plasma clearance for subjects (0.4) was smaller (p less than 0.05) than that for patients. The slower rate of flecainide elimination from plasma in patients is likely due to reduced hepatic biotransformation. In patients with cirrhosis, plasma levels of flecainide may accumulate to unacceptably high levels with usual dosage regimens.     

Reduction in biliary excretion of ceftriaxone by diclofenac in rabbits.

The effects of diclofenac, a nonsteroidal anti-inflammatory drug, on biliary excretion of ceftriaxone were evaluated in rabbits. In a previous study, we demonstrated that diclofenac increased the extravascular diffusion and antibacterial efficacy of ceftriaxone without any effect on serum protein binding and urinary excretion of this antibiotic. We perfected a surgical procedure that allowed the study of biliary secretion in conscious rabbits with a stable hemodynamic state. The kinetic study was carried out on the fourth day of treatment with ceftriaxone alone (30 mg/kg per day given intramuscularly; group 1) or combined with diclofenac (1.5 mg/kg per 12 h given intramuscularly; group 2). Cumulative biliary excretion of ceftriaxone over 6 h was significantly reduced in group 2 (5,291.6 +/- 2,017.5 micrograms in group 1 versus 1,379.1 +/- 567.1 micrograms in group 2). This phenomenon occurred without any change in biliary flow. Indocyanine green clearance (20 mg/kg) increased in animals treated with ceftriaxone alone compared with the saline-treated control group (55.04 +/- 4.68 versus 33.29 +/- 7.52 ml/min per kg, respectively). Diclofenac alone caused a significant decrease in indocyanine green clearance compared with clearance in controls (25.05 +/- 4.74 versus 33.29 +/- 7.52 ml/min per kg), and indocyanine green clearance appeared not significantly different from control values in animals receiving ceftriaxone plus diclofenac. These results suggest that (i) ceftriaxone could increase hepatic blood flow and (ii) reduction of the hepatic clearance of ceftriaxone by diclofenac may be due to hepatic hemodynamic variations involving diclofenac inhibition of prostaglandin synthesis, although an interaction of diclofenac with hepatic uptake of ceftriaxone cannot be ruled out.     

Beta-adrenergic blockade affects initial drug distribution due to decreased cardiac output and altered blood flow distribution

Beta-adrenergic receptor blockers decrease intravenous anesthetic dose requirements. The present study determined the effect of propranolol on indocyanine green and antipyrine disposition from the moment of rapid intravenous injection. Anti-pyrine is a physiological marker that distributes to a volume as large as total body water in a blood flow-dependent manner and is a pharmacokinetic surrogate for many lipophilic drugs, including intravenous anesthetics. Antipyrine and indocyanine green disposition were determined twice in five healthy adult males in this Institutional Review Board-approved study, once during propranolol infusion. After rapid indocyanine green and antipyrine injection, arterial blood samples were collected frequently for 2 min and less frequently thereafter. Plasma indocyanine green and antipyrine concentrations were measured by high-performance liquid chromatography. Indocyanine green and antipyrine disposition were characterized, using SAAM II, by a recirculatory pharmacokinetic model that describes drug disposition from the moment of injection. Parameters were compared using the paired t test. The disposition of indocyanine green demonstrated that propranolol decreased cardiac output at the expense of the fast peripheral (nonsplanchnic) intravascular circuit. The area under the antipyrine concentration versus time relationship was doubled for at least the first 3 min after injection due to both decreased cardiac output 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. The increase in antipyrine area under the curve due to propranolol-induced alteration of initial antipyrine disposition could explain decreased intravenous anesthetic dose requirements in the presence of beta-adrenergic receptor blockade.     

Interaction between metronidazole and drugs eliminated by oxidative metabolism

Single-dose kinetics of 0.1 mg/kg intravenous diazepam, 10 mg/kg oral antipyrine, and 300 mg oral phenytoin were followed in healthy subjects before and after 400 mg metronidazole twice a day for 5 days. When data before metronidazole dosing were compared with those after metronidazole dosing, there were no changes in total plasma clearance of diazepam (0.53 and 0.65 ml/min/kg), antipyrine (39.0 and 38.0 ml/min/kg), or phenytoin (0.56 and 0.55 ml/min/kg). Plasma t 1/2s and volumes of distribution of the three drugs tested were not affected by metronidazole, but urinary excretion of 4-hydroxyantipyrine decreased after metronidazole dosing. There was no change in the elimination of phenytoin as its hydroxylated metabolite after metronidazole. It is concluded that, at therapeutic concentrations, metronidazole does not significantly inhibit oxidative drug metabolism.