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The elimination of bromsulphthalein (BSP) and indocyanine green (ICG) from plasma and urinary excretion of BSP were investigated in healthy cats. At 5 mg kg-1, BSP elimination fitted a two-compartment open model, with mean t1/2 beta of 7.1 (SD 2.5) minutes. A tendency for slower elimination of BSP at 10 mg kg-1 suggested saturation of excretory mechanisms, while at 2 mg kg-1 accurate dosing and assay of low BSP concentrations were difficult. Urinary recovery of BSP at 5 mg kg-1 was 0.01 to 0.13 per cent of the total dose. Plasma ICG (0.5 mg kg-1) data fitted a one-compartment open model, with mean t1/2 2.7 (SD 1.0) minutes. In cats, retention tests are more attractive than clearance tests because fewer blood collections are necessary. Proposed reference values are under 3.6 per cent retention of BSP (5 mg kg-1) at 30 minutes and under 17.5 per cent retention of ICG (0.5 mg kg-1) at 15 minutes. At present economic and technical factors favour BSP over ICG.

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For several drugs metabolized by the liver, higher dosages (mg/kg body weight) are required in children to attain serum concentrations comparable to those in adults. Indocyanine green (ICG), a commonly used model substrate for hepatic elimination of high intrinsic clearance drugs, has been extensively evaluated in adults but not in children. We evaluated the disposition of ICG in 115 children with leukemia and nine healthy adult volunteers. The mean (SD) ICG plasma clearance (CLp) for all 115 children (age 0.9-17.8 years) was significantly greater (p = 0.0006) than for adults [14.8 (7.8) versus 10.6 (2.4) mL/min/kg]. When clearances from only children less than 10 years of age (N = 85) were compared with those from adults, the difference was even greater [15.6 (7.3) versus 10.6 (2.4) mL/min/kg; p = 0.0001]. However, when ICG CLp was normalized to body surface area, values for children did not differ significantly from adults [378 (204) versus 422 (102) mL/min/m2]. These data provide insight as to why dosage (mg/kg) requirements of certain drugs are higher in children.

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A rapid and sensitive reversed-phase HPLC assay employing fluorescence detection was developed for quantitating indocyanine green (ICG) in rat plasma. Sample preparation entailed precipitation of plasma proteins with acetonitrile prior to injection on the column. The assay was linear from 0.4 to 200 micrograms/mL, with a detection limit of 3 ng on column. The plasma concentration-time profile of ICG was characterized by this HPLC method and compared with the traditional spectrophotometric assay following iv bolus and iv infusion administration of 5 mg/kg of ICG to rats. Concentrations of ICG obtained using the spectrophotometric assay were consistently higher than those determined by HPLC. In animals receiving ICG by infusion, the maximum difference between the two assays was observed 1 min post-infusion and became negligible by 5 min post-infusion. The calculated pharmacokinetic parameters for ICG, systemic clearance and apparent volume of distribution, were higher using the HPLC assay as compared with the spectrophotometric procedure. The data suggest that a biotransformation or degradation product of ICG is formed in the rat and interferes with the determination of ICG by the spectrophotometric assay. Since the HPLC assay is specific for the parent dye, it is suggested that this assay method be used when determining pharmacokinetic parameters of ICG in rats.

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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.

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The pharmacokinetics of Indocyanine Green (ICG) has been studied in 15 patients given 0.5, 1.0 and 2.0 mg.kg-1. The plasma disappearance and biliary excretion rate were measured in patients with tightly fitting catheters under slight negative pressure in order to achieve complete collection of bile. Recovery of unchanged ICG in bile over 18 h after the i.v. injection was 80% of the dose in all three dose groups. Plasma disappearance in all 3 groups was biphasic, showing an initial phase with a t1/2 of 3-4 min and a secondary phase with a dose-dependent apparent t1/2 of 67.6, 72.5 and 88.7 min, respectively. After 0.5 and 1.0 mg.kg-1 the biliary excretion rate curves showed an ascending phase with a mean t1/2 of 5 min and a descending phase with a mean t1/2 of 72 min. It was inferred that the secondary component of the plasma-decay mainly reflected the biliary excretion rate. After 2.0 mg.kg-1 in some patients the biliary excretion curve showed features of saturation; the t1/2 of the descending phase ranged from 73 to 440 min, and the time of maximal excretion was increased from 1.3 to 2.7 h after injection, whilst the mean maximal excretion rate was in the same range as the excretion rate after the 1.0 mg.kg-1 dose. The non-linear pharmacokinetics was only moderately reflected in the measured plasma disappearance patterns. Two compartment analysis of the plasma levels indicated a clearance of 230-260 ml.min-1, whereas the clearance conventionally calculated from the initial t1/2 was 475 ml.min-1.(ABSTRACT TRUNCATED AT 250 WORDS)

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Time-associated changes in the disappearance rate of indocyanine green from the blood (K.ICG) as an index of liver function, were studied. Blood was drawn 5 times at 3-minute intervals from 32 patients. Early, intermediate, and late K.ICG values were 0.087 +/- 0.040, 0.082 +/- 0.038, and 0.076 +/- 0.033 min-1, respectively, showing serial decreases. When blood was drawn 8 times at 2-minute intervals from 22 other patients, the means of the K.ICG values at 11 time points showed a nearly linear relationship (r = -0.986). These findings indicated that K.ICG is approximated by a linear function of time, K(t) = -K'.t + K0. According to this function, K.ICG is considered to decrease by 1.96% every minute. The K.ICG value determined by the conventional method is, therefore, a mean disappearance rate of 15 minutes, and K0 is considered to reflect the initial reaction speed.

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The purposes of the present investigation were (i) to directly compare in man, indocyanine green (ICG) plasma concentrations analyzed by high performance liquid chromatography (HPLC) vs. spectrophotometry; (ii) to evaluate whether the pharmacokinetic parameters generated for ICG from a clinical study are assay-dependent; (iii) to examine whether the method of pharmacokinetic analysis affects the magnitude of any assay-related differences observed in ICG's pharmacokinetic parameters; and (iv) to evaluate whether assay methodology and/or method of pharmacokinetic analysis affect the conclusions derived from a clinical study employing ICG as a marker for hepatic blood flow (HBF). Plasma samples obtained from a clinical study designed to assess the effects of cimetidine and posture on HBF were analyzed by spectrophotometry and HPLC. The spectrophotometric method overestimated ICG plasma concentrations when compared to HPLC. This finding is consistent with the observations of others suggesting the presence of a chemical impurity in the commercial ICG preparation. Data generated by the spectrophotometric method produced lower ICG clearance and HBF estimates and a longer ICG half-life regardless of the method of pharmacokinetic analysis. The method of pharmacokinetic data analysis had no effect on any pharmacokinetic parameter. The experimental conclusions derived from the clinical study were not affected by either analytical methodology or method of data analysis.

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Indocyanine green (ICG) and (+)-propranolol kinetics were determined in the rat following moderate (50%) blood exchange with either Fluosol-DA or 0.9% NaCl (saline). Rats received an intravenous ICG dose (5 mg kg-1) before an intravenous dose of (+)-propranolol (2.5 mg kg-1) 0.5, 24, 48 or 72 h after haemodilution and were compared with non-exchanged controls. Haemodilution with Fluosol-DA reduced the ICG elimination rate constant during the first 24 h while a significant reduction was seen 48 h after normal saline exchange. ICG clearances tended to be less than the control value, and were significantly reduced only at 24 h after Fluosol-DA exchange due to a reduced Varea. (+)-Propranolol half-life was significantly increased 48 and 72 h after saline exchange; (+)-propranolol clearance was also significantly reduced 72 h after Fluosol-DA exchange. ICG clearance may be reflecting a hypovolaemic change which occurs after haemodilution, which would reduce the hepatic blood flow. However, (+)-propranolol clearance was not altered, suggesting that the hepatic blood flow is not changed. It is possible that ICG clearance is changed due to alterations in its extraction ratio instead of hepatic blood flow changes.

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Patients with premature ventricular contractions are also frequently hypoxemic (HO) and/or hypercapnic (HC). The aims of the present study were to document the effect of HO and/or HC on the kinetics of lidocaine, a first choice drug for the i.v. treatment of premature ventricular contractions, and on indocyanine green (ICG), another flow-dependent drug. For this purpose, five groups of rabbits were used: a control group received 2.5 mg/kg i.v. of ICG followed, 30 min later, by 7.5 mg/kg of lidocaine as a bolus. Four other groups received lidocaine as an infusion (261 micrograms/min/kg) for 255 min and ICG (249 micrograms/min/kg) for 8 min, the latter beginning 180 min after the start of the lidocaine infusion. The controls and one test group receiving the lidocaine infusion were breathing air (PaO2 = 89 +/- 2 (S.E.M.) and PaCO2 = 20 +/- 1 mm Hg); the second test group had HO (PaO2 = 51 +/- 1 mm Hg), a third group HC (PaO2 = 68 +/- 1 mm Hg) and the fourth HO combined with HC (HOHC) (PaO2 = 53 +/- 1 and PaCO2 = 61 +/- 2 mm Hg). Multiple blood samples were drawn. Lidocaine and its metabolites and ICG were assayed by high-performance liquid chromatography. Lidocaine volume of distribution was not affected by HO and/or HC. Compared to control values, the clearance of infused lidocaine (CIL) tended to decrease from 65 +/- 2 to 53 +/- 3 ml/min/kg. In animals with HO, HC and HOHC, CIL was 49 +/- 6, 45 +/- 5 and 46 +/- 3 ml/min/kg, respectively, these values not being significantly different from CIL.(ABSTRACT TRUNCATED AT 250 WORDS)

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With this fluorometric method for measuring indocyanine green (ICG) in biological fluids, the limit of detection is an order of magnitude lower than for the traditional spectrophotometric procedure. The excitation and emission maxima are 780 and 810 nm, respectively. Agreement was excellent (r = 0.998) between direct results by this method and those by a liquid-chromatographic procedure with spectrophotometric detection. ICG breaks down in aqueous solution; the degradation products can be detected with liquid-chromatographic/spectrophotometric methods, but because the metabolites are not fluorescent, they do not interfere in the method present here. The increased specificity and sensitivity of this method should permit much more complete analysis of the kinetics of ICG disposition.

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Theophylline (oxidative phase I metabolism) is biotransformed by the liver at an increasingly delayed rate with advancing age. Hymecromone (phase II metabolism) does not display any dependence of glucuronidisation on age. The indocyanine green half-life and the galactose elimination capacity show a highly significant dependence on age. Drugs with flow-limited elimination or mainly oxidative phase I biotransformation should be administered with reduced dosage level while monitoring the serum concentration levels. Drugs that are transformed via phase II reactions usually do not require dosage adjustment.

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Experiments were performed to determine the validity of the indocyanine green (ICG) clearance technique, with and without allowances for incomplete hepatic extraction, as an estimate of hepatic plasma flow. This technique was compared with that of directly measured hepatic blood flow using a hepatic venous long-circuit preparation in the anesthetized cat. This preparation allowed direct measurement and alteration of hepatic blood flow and collection of arterial, portal, and hepatic venous blood samples without depletion of the animal's blood volume. Measurements of ICG by spectrophotometry and high-pressure liquid chromatography (HPLC) were equally accurate, but the HPLC was 100 times more sensitive and allowed smaller sample volumes. It was determined that systemic clearance of ICG after a bolus dose (1.3 mumol/kg) was much smaller than hepatic blood flow. Allowance must be made for the incomplete extraction. When the clearance was multiplied by extraction, mean estimated hepatic plasma flow exceeded the measured flow values by 20-30%, and this difference was attributed to temporary extrahepatic distribution. In all experiments estimated hepatic plasma flows were highly variable, and reasons for this are discussed. In hepatectomized cats ICG was found to be distributed into extrahepatic tissues.

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Enprostil, an orally active prostaglandin E2 analog, is undergoing clinical trials in the treatment of peptic ulcer disease. Because results of animal studies suggested that prostaglandins might affect both hepatic drug metabolizing ability and hepatic blood flow, the effects of enprostil on drug elimination were studied and compared with those of the standard antiulcer drug cimetidine in a double-blind, randomized, crossover study of nine normal subjects. Cimetidine reduced the oral clearance of propranolol by 50%, consistent with the inhibition of drug metabolism reported in previous studies. On the other hand, enprostil had no effect on propranolol elimination. Neither drug altered liver blood flow as assessed either by the clearance of indocyanine green or by the technique of dual route of administration of propranolol. Thus in contrast to cimetidine, enprostil had no effect on hepatic drug metabolism.

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The pharmacokinetic values of thiacetarsamide (2.2 mg/kg) were determined in 6 healthy dogs after IV injection. A semilogarithmic plot of serum concentration vs time indicated that the 2-compartment open model best described thiacetarsamide disposition. A least-squares log linear regression microcomputer program was used to calculate the pharmacokinetic values. The mean elimination-phase half-life and clearance rate were 43 minutes and 200 ml/kg/min, respectively. Wide ranges in values were seen for the half-life (20.5 to 83.4 minutes) and the clearance rate (80.0 to 350.0 ml/kg/min). Before thiacetarsamide was given to the dogs, indocyanine green (ICG), an anionic dye that is eliminated almost entirely by hepatobiliary excretion, was administered IV at a dosage of 0.5 mg/kg of body weight. The half-life of ICG was 7.4 minutes, and the clearance rate was 8.43 ml/kg/min. There was a significant (P less than 0.01) correlation between the half-lives of thiacetarsamide and ICG, but not between the clearance rates. The variations in ICG half-lives and clearance rates were less than those seen for thiacetarsamide.

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The effect of pentobarbitone anaesthesia and the effect of hypothermia associated with the anaesthesia on the blood clearance of indocyanine green (ICG) and of S(-)-acenocoumarol (AC) was investigated in male Wistar rats using the constant rate infusion technique. During anaesthesia, body temperature was regulated by heat supply. At normothermia (rectal temperature of 37.5 degrees C), pentobarbitone anaesthesia decreased ICG clearance from 8.0 +/- 1.7 ml min-1 (mean +/- s.e.m., n = 3) in the conscious state to 4.3 +/- 0.6 ml min-1 and AC clearance from 4.9 +/- 0.4 ml min-1 to 3.4 +/- 0.3 ml min-1. Hypothermia further reduced the clearances of the compounds to 0.9 +/- 0.1 and 2.5 +/- 0.2 ml min-1 for ICG and AC, respectively. The effect of hypothermia was reversible. The results show that pharmacokinetic constants obtained in the anaesthetized animal may differ greatly from those in the conscious one. If pharmacokinetic experiments are performed in the anaesthetized animal, body temperature should be controlled and a slight hyperthermia is most favourable. Our pharmacokinetic data on ICG seriously question the use of this drug to estimate liver blood flow in the rat.

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Mice that had received 10(6) P388 leukemia cells IV 8 days previously exhibited a decrease in the components of the hepatic microsomal mixed function oxidase, with a 58% decrease in cytochrome P-450, and up to a 60% decrease in hepatic microsomal metabolism of biphenyl. Liver weight was increased by 49% due to infiltration of the liver with leukemic cells. Changes in liver drug-metabolizing activity and liver weight were not seen 6 days after administration of P388 leukemia. There was a small increase in serum liver enzyme but no increase in total serum bilirubin in tumor-bearing mice. In vivo total-body plasma clearance of cyclophosphamide, a drug metabolized by hepatic cytochrome P-450, was decreased to 53 ml/min/kg in mice that had received P388 cells 8 days earlier, as against 97.2 ml/min/kg in control mice. Cytochrome P-450-independent metabolism of [14C]5-fluorouracil, measured by means of [14C]CO2 in the breath over 3 h, was decreased to 21% of the dose administered by 8 days after tumor cell administration, compared with 31% of the dose in control mice. P388 leukemia cells growing in the ascitic form in the intraperitoneal cavity of mice did not release an inhibitor of 5-fluorouracil metabolism into the ascitic fluid. Total-body plasma clearance of indocyanine green was decreased to 11 ml/min/kg by 8 days after P388 cell administration, compared with 36 ml/min/kg in control mice. The decrease in indocyanine green clearance might reflect a decrease in hepatic blood flow in the tumor-bearing mice. A possible explanation for the decrease in hepatic drug metabolism caused by P388 leukemia is that the hepatocytes are deprived of oxygen and nutrients by the tumor in the liver, coupled with or caused by a physical obstruction of hepatic blood flow.

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Fasting is associated with unconjugated hyperbilirubinemia in several species, including the horse. Studies in ponies showed that a 3-day fast decreased plasma clearance of bilirubin, cholic acid, and sulfobromophthalein (BSP). Since these organic anions are conjugated with different substrates, it is possible that observed differences in plasma clearance result from a general decrease in hepatic conjugating capacity during the animals' fasting. To test this hypothesis, the effects of a 3-day fast on plasma clearance of IV injected BSP (4.4 to 5.1 mg/kg), which is conjugated to glutathione, and indocyanine green (ICG; 0.8 to 1.1 mg/kg), which is not conjugated, were studied in 10 healthy horses and 2 ponies with diverted enterohepatic circulations (indwelling T tubes). Blood samples were obtained for 30 minutes after injection, and bile samples from ponies were obtained for 3 hours. Fasting increased plasma bilirubin concentration in all animals studied (from 1.03 +/- 0.337 mg/dl in control animals to 3.49 +/- 1.01 mg/dl in fasted animals). Kinetic values of ICG disappearance were determined from single exponential functions, and those for BSP were determined from both single and curvilinear (2-exponential) functions. Plasma clearance of BSP in fed horses (8.65 +/- 1.02 ml X min-1 X kg-1) was greater than clearance of ICG (3.54 +/- 0.67 ml X min-1 X kg-1), results similar to those reported in dogs, cats, rats, and persons. Fasting significantly decreased fractional plasma disappearance rate of both BSP (-36%) and ICG (-58%) and similarly reduced plasma clearance (BSP,-48%; ICG,-55%).(ABSTRACT TRUNCATED AT 250 WORDS)

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The mechanism by which the mean blood clearance (CLtot,B) of indocyanine green (ICG) was reduced in cirrhotic patients was examined pharmacokinetically. It was demonstrated that the reduction in the CLtot,B of ICG in cirrhosis would be mainly due to the decrease in the hepatic uptake clearance and partly due to the increase in the efflux clearance from the liver to plasma. It is suggested that the decrease in the hepatic uptake clearance in cirrhosis mainly reflects the decrease in the intrinsic clearance of hepatic uptake rather than the decrease in hepatic blood flow.

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