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Pharmacokinetics of biliary excretion in man. Plasma disappearance of indocyanine green in relation to its excretion rate
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PHARMACOKINETICS OF BILIARY EXCRETION IN MAN. PLASMA DISAPPEARANCE OF INDOCYANINE GREEN IN RELATION TO ITS EXCRETION RATE D.K.F. Meijer, B. Weert and G.A. Vermeer State University of Groningen, Department of Pharmacology and Pharmacotherapeutics, Ant. Deusinglaan 2, 97]3 AW Groningen, The Netherlands.
In spite of the extensive use of indocyanine green (ICG) in studies on blood circulation and hepatic clearance function, no detailed information is available on its biliary excretion profile in man. We studied the plasma disappearance in relation to its biliary excretion rate in 12 patients with biliary catheters 48 hours after cholecystectomy. After an i.v. bolus injection of 0.5 mg/kg, a monoexponential plasma decay was found with a t~ of 4.1+0.5 min (n=6). Distribution volume was 2.6+0.3 liters per 70 kg. Plasma clearance was 426+64 m~/min per 70 kg, indicating that clearance i~ only partly flow limited. In contrast to the plasma disappearance curve, the biliary excretion race curve exhibited a biexponential pattern showing an ascendin8 phase with a t~ value of 5-]0 min (after correction for dead space effects) and a descending phase ranging from 62-138 min (mean 73.0+17.0 min). Total recovery of unchanged ICG in bile was 99+9% of the dose. These data indicate that biliary drainage, that was performed under negative pressure, was rather complete. The slow component in the biliary excretion rate curve was not reflected in the plasma decay at the dose of 0.5 mg/kg, indicating that no appreciable bidirectional transport between plasma and liver occurs and hepatic uptake of ICG seems irreversible. This may be related to the positively charged groups in the ICG molecule in addition to its anionic sulfonic acid groups and/or to extensive intracellular binding. However at doses of 1.0 and 2.0 mg/kg of ICG a secondary phase in the plasma decay curves with a t½ of 50-100 min could be observed (n=4 patients) at relatively low concentrations. It is concluded that pharmacokinetics of ICG should be described by 2-compartmental model with an extremely low k21 rate conscant. Only at doses exceeding 1.0 mg/kg a secondary phase can be reliably detected with routine spectrophotometric methods. A dose of 2.0 mg/kg therefore is advisable for adequate measurement of the various hepatobiliary transport steps as well as hepatic storage function.
I82:EHUM ACUTE PHASE PROTEINS (APPs) IN ACUTE AND CHRONIC LIVER DISEASE. R. Meliconi,O. Parracinc F'. Miglio,M.L. Schiattone*,F. Chiodo'',G. Verucchi4*,A. Facchini,M. Martuzzi',G. Gasbarrini. l[I Patologia Medica e I Clinica Medica, *'Ist. Malattie InfeCtive, Universitfi di Bologna;*Patologia Clinica, Osp. Maggiore, Bologna.
Serum levels of APPs undergo marked changes during acute and chronic inflammation and tissue damage. So far littie is known about APP levels in liver disease and their ciinicaI significance is still debated. Therefore we evaluated the levels of 6 APPs (~-Reactive Protein, Huptoglobin,al acid glycoprotein,a~ antitrypsin,o 2 macroglobulin, transferrin) determined by means of nephelometric assay in: 3~ patients with acute viral hepatitis (12 type A, 12 B, 12 nonAnonB; 129 sera for follow-ups), 31 CAH (20 type B, 4 cryptogenic, 7 autoimmune) 14 PB: and q ~Vilson's dlsease. Our normal range was obtained testing 200 healthy subjects (100 females). As positive controls we tested sera from 20 patients with Rheumatoid Arthritis (RA) and II wlth Inflammatory Bowel Disease (IBD). In acute hepatitis course neither significant alterations of the mean values or APPs nor any relation to AST levels was found. On the other hand {n chronic patients: a) APP levels in viral CAH, cryptogenic CAH and Wilson's disease were si*~111f'~-antl.y lower than in healthy subjects, autoimmune :AH, PBC, RA, IBD; b) ~ antitrypsin 1 ,~:,d ~ macrogl,.~bulin leve[~; Jr, autolmmune CAH and PBC were significantly higher than in normal .'~rl!~';~Is. ('~ur d;,t:J provide a clear-cut "liver pattern" of APPs in chronic patients. The striVln~ dirre{-ence between viral and autoimmune CAH or PBC resemble the behaviour of (auto)immu,,' r'eactJons in these diseases. Further studies are needed to elucidate the relations between AP['~; and immune rea,Ttions in ~AH.
$91
PHARMACOKINETICS OF BILIARY EXCRETION IN MAN. PLASMA DISAPPEARANCE OF INDOCYANINE GREEN IN RELATION TO ITS EXCRETION RATE D.K.F. Meijer, B. Weert and G.A. Vermeer State University of Groningen, Department of Pharmacology and Pharmacotherapeutics, Ant. Deusinglaan 2, 97]3 AW Groningen, The Netherlands.
In spite of the extensive use of indocyanine green (ICG) in studies on blood circulation and hepatic clearance function, no detailed information is available on its biliary excretion profile in man. We studied the plasma disappearance in relation to its biliary excretion rate in 12 patients with biliary catheters 48 hours after cholecystectomy. After an i.v. bolus injection of 0.5 mg/kg, a monoexponential plasma decay was found with a t~ of 4.1+0.5 min (n=6). Distribution volume was 2.6+0.3 liters per 70 kg. Plasma clearance was 426+64 m~/min per 70 kg, indicating that clearance i~ only partly flow limited. In contrast to the plasma disappearance curve, the biliary excretion race curve exhibited a biexponential pattern showing an ascendin8 phase with a t~ value of 5-]0 min (after correction for dead space effects) and a descending phase ranging from 62-138 min (mean 73.0+17.0 min). Total recovery of unchanged ICG in bile was 99+9% of the dose. These data indicate that biliary drainage, that was performed under negative pressure, was rather complete. The slow component in the biliary excretion rate curve was not reflected in the plasma decay at the dose of 0.5 mg/kg, indicating that no appreciable bidirectional transport between plasma and liver occurs and hepatic uptake of ICG seems irreversible. This may be related to the positively charged groups in the ICG molecule in addition to its anionic sulfonic acid groups and/or to extensive intracellular binding. However at doses of 1.0 and 2.0 mg/kg of ICG a secondary phase in the plasma decay curves with a t½ of 50-100 min could be observed (n=4 patients) at relatively low concentrations. It is concluded that pharmacokinetics of ICG should be described by 2-compartmental model with an extremely low k21 rate conscant. Only at doses exceeding 1.0 mg/kg a secondary phase can be reliably detected with routine spectrophotometric methods. A dose of 2.0 mg/kg therefore is advisable for adequate measurement of the various hepatobiliary transport steps as well as hepatic storage function.
I82:EHUM ACUTE PHASE PROTEINS (APPs) IN ACUTE AND CHRONIC LIVER DISEASE. R. Meliconi,O. Parracinc F'. Miglio,M.L. Schiattone*,F. Chiodo'',G. Verucchi4*,A. Facchini,M. Martuzzi',G. Gasbarrini. l[I Patologia Medica e I Clinica Medica, *'Ist. Malattie InfeCtive, Universitfi di Bologna;*Patologia Clinica, Osp. Maggiore, Bologna.
Serum levels of APPs undergo marked changes during acute and chronic inflammation and tissue damage. So far littie is known about APP levels in liver disease and their ciinicaI significance is still debated. Therefore we evaluated the levels of 6 APPs (~-Reactive Protein, Huptoglobin,al acid glycoprotein,a~ antitrypsin,o 2 macroglobulin, transferrin) determined by means of nephelometric assay in: 3~ patients with acute viral hepatitis (12 type A, 12 B, 12 nonAnonB; 129 sera for follow-ups), 31 CAH (20 type B, 4 cryptogenic, 7 autoimmune) 14 PB: and q ~Vilson's dlsease. Our normal range was obtained testing 200 healthy subjects (100 females). As positive controls we tested sera from 20 patients with Rheumatoid Arthritis (RA) and II wlth Inflammatory Bowel Disease (IBD). In acute hepatitis course neither significant alterations of the mean values or APPs nor any relation to AST levels was found. On the other hand {n chronic patients: a) APP levels in viral CAH, cryptogenic CAH and Wilson's disease were si*~111f'~-antl.y lower than in healthy subjects, autoimmune :AH, PBC, RA, IBD; b) ~ antitrypsin 1 ,~:,d ~ macrogl,.~bulin leve[~; Jr, autolmmune CAH and PBC were significantly higher than in normal .'~rl!~';~Is. ('~ur d;,t:J provide a clear-cut "liver pattern" of APPs in chronic patients. The striVln~ dirre{-ence between viral and autoimmune CAH or PBC resemble the behaviour of (auto)immu,,' r'eactJons in these diseases. Further studies are needed to elucidate the relations between AP['~; and immune rea,Ttions in ~AH.
$91