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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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The pharmacokinetics of the long-acting anticholinesterase drug, galanthamine, were investigated in eight patients. After i.v. injection of 0.3 mg kg-1, the decrease in the serum concentration of galanthamine followed a biexponential curve. The serum concentration decreased rapidly from 543 +/- 47 ng ml-1 to 128 +/- 14 ng ml-1 between 2 and 30 min with a T1/2 alpha of 6.42 +/- 2.15 min, and then declined more slowly with a T1/2 beta of 264 +/- 28 min. Total serum clearance of galanthamine amounted to 5.37 +/- 0.87 ml min-1 kg-1, and the renal clearance was 1.36 +/- 0.10 ml min-1 kg-1. The cumulative urinary excretion of galanthamine between 0 and 48 h after injection amounted to 28.0 +/- 5.4% of the administered dose. The biliary excretion of galanthamine during 24 h amounted to 0.2 +/- 0.1% of the dose. There was no evidence of glucuronide or sulphate conjugation of galanthamine.

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In bile specimens from postoperative patients with biliary drainage following cholecystectomy, in addition to unchanged dibromosulfophthalein (DBSP), a single polar metabolite of DBSP was found after i.v. injection of 5 mg/kg of the diagnostic dye. This metabolite, which has not previously been detected, was resistant to beta-glucuronidase and arylsulfatase and was remarkably stable in strongly acid and alkaline solutions. It exhibited the same spectrum and colour change interval as unchanged DBSP. Further studies of its identity revealed that it gave a ninhydrin-positive reaction and that its Rf-value on TLC could be restored by Raney-nickel reduction. Amino-acid analysis after reduction and acid hydrolysis showed an increase in glutamic acid and alanine that can be considered as splitting products of conjugated glutathione following these procedures. Estimation of the quantity of this possible glutathione conjugate indicates that it is formed less rapidly than the glutathione derivative of the tetrabromoanalogue BSP, and that it represents up to 25% of the total dye excreted in bile. The observed metabolism of DBSP in man may complicate its use in the study of hepatic transport function, and negates the previous assumption that, as in certain other animal species, the dye is excreted unchanged.

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The plasma clearance of pancuronium in patients with extrahepatic cholestasis was 16% lower than in a control group (1.47 +/- 0.11 ml min-1 kg-1 v. 1.76 +/- 0.21 ml min-1 kg-1), but the difference was not significant. A significant increase in the elimination half-life T 1/2 beta of pancuronium (from 141 to 224 min) and a significant increase in the volume of the peripheral compartment (V2) was found in patients with extrahepatic cholestasis when compared with control patients. There was a significantly lower cumulative biliary excretion of pancuronium (0.3 +/- 0.3% v. 10.9 +/- 3.2% in the controls) during the 48-h period of observation. The biotransformation and cumulative urinary excretion patterns of pancuronium revealed no significant differences between the two groups of patients. The increase of T 1/2 beta pancuronium in patients with extrahepatic cholestasis was mainly a consequence of the increase in the volume of distribution. No significant differences in the plasma clearance, T 1/2 beta or in the volume of distribution were observed with gallamine in the patients with extrahepatic cholestasis when compared with the control group. The cumulative urinary excretion of gallamine during 48 h in both groups of patients was approximately 100%. We concluded that in patients with cholestasis and normal glomerular filtration, gallamine is probably more reliable than pancuronium for neuromuscular blockade.

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To compare the pharmacokinetics of d-tubocurarine and metocurine in man, concentrations of 3H-d-tubocurarine and 14C-metocurine (0,0,N-trimethyl-tubocurarine) in plasma, urine and bile were determined after intravenous administration of d-tubocurarine, 0.15 mg/kg (five patients), and metocurine, 0.05 mg/kg (five patients), in patients anesthetized with thiopental and nitrous oxide for cholecystectomy. Plasma disappearances of both drugs were triexponential, with mean terminal half-lives of 346 and 217 min for d-tubocurarine and metocurine, respectively. By ion-pair thin-layer chromatography, no metabolite of either compound was found in urine or bile. Renal excretions 48 hours after injection ranged from 46 to 95 per cent of the dose for d-tubocurarine and from 46 to 58 per cent for metocurine. Mean total-body clearances were 56 and 96 ml/min for d-tubocurarine and metocurine, respectively. Biliary elimination of d-tubocurarine was greater than that of metocurine: within 48 hours 11.8 and 2.1 per cent of the doses were excreted in bile, respectively. The observed differences in total-body clearances and volumes of distribution (V1) may be partly explained by greater protein binding of d-tubocurarine. The results indicate that biliary excretion is an alternative route of elimination for d-tubocurarine only. Also, d-tubocurarine is less dependent on renal excretion for its elimination, and probably is preferable to metocurine for use in patients with renal failure.

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The fate of gallamine triethiodide has been investigated in patients undergoing cholecystectomy with choledochostomy (group I), pelvic operations (group II) and orthopaedic operations (group III). Following a single i.v. injection of gallamine 2.5 mg kg(-1) the disappearance of the drug from the serum occurred in three phases with half-lives of less than 5, 30, 138 min, less than 5, 39, 141 and less than 5, 48, 144 min in the respective groups. Twenty-four hours after injection the renal excretion of the unchanged drug was 53% (15-100%) of the administered dose in group I, 67% (40-90%) in group II and 95% (89-100%) in group III. The biliary excretion of gallamine appeared to be negligible in man. The relationship between renal excretion and duration of action of gallamine, and the influence of some intraoperative factors on drug disposition, are discussed.

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