Indocyanine green pharmacokinetics and portal vein administration
The clearance of indocyanine green (ICG) following systemic administration is influenced by many factors including cardiac output, hepatic blood flow, intrinsic hepatic clearance and protein binding. Drugs for which the intrinsic hepatic clearance exceeds hepatic blood flow are useful as markers of hepatic blood flow. Hepatic blood flow has been estimated using different approaches. The distribution of ICG is not affected by cardiac output or hepatic blood flow when ICG is administered via the portal vein. If information concerning the intrinsic clearance of ICG can be obtained, it may be possible to commence treatment for hepatic disorders earlier.
Progress in surgical treatment requires improvement of perioperative management. Percutaneous transhepatic portography (PTP) and the insertion of portal vein catheters are useful procedures in liver surgery, and make possible clinical pharmacokinetic assessment of liver function.
We hypothesized that the clearance of ICG following portal vein injection (CLpv) would be more useful than that after peripheral vein injection (CLiv) for evaluating the intrinsic clearance of ICG and hepatic blood flow.
Eight patients were studied. The study was approved by the Institutional Human Research Committee of Osaka City University Hospital, and informed consent was obtained from each patient. Preoperative laboratory data revealed mild liver dysfunction or cirrhosis in each patient. Hepatic cirrhosis was confirmed by histological examination of liver specimens.
Each patient underwent PTP under local infiltrative anaesthesia supplemented by intravenous analgesics (Stage I). ICG (25 mg) was injected into a peripheral vein before PTP, and then into the portal vein after PTP. ICG was given as a bolus with at least 30 min separating the two injections. Arterial blood samples were withdrawn through the radial artery for h.p.l.c measurement of ICG concentrations in plasma at 2, 5, 7, 10, 12, 15, 17, 20, 25, and 30 min after each injection. One week later, enflurane was given to patients on the day of operation. Secobarbitone (100 mg) and 0.5 mg of atropine sulphate were given intramuscularly 1 h before operation. Anaesthesia was induced with 5 mg kg−1 of thiopentone and patients were intubated using 0.1 mg kg−1 of vecuronium bromide. The muscle relaxant was supplemented during operation when necessary, and its effect was reversed using 2 mg of neostigmine with 1 mg of atropine. No other medication was given perioperatively to any patient. ICG (25 mg) was given as a bolus into a branch of the portal vein (a mesenteric vein) and then into a peripheral vein during anaesthesia, 30 min apart between two injections (Stage II) and after partial hepatectomy (Stage III). Twelve hours after surgery, the same amount of ICG was administered via a peripheral vein to all patients, and also into the portal vein in three of the eight patients (Stage IV). Blood samples were obtained using the same schedule as during PTP.
Non-compartmental analysis was applied to the ICG time-concentration data obtained. The concentration measured after the second injection was corrected by three steps, since the drug remaining after the first injection might have affected the concentration of the drug after the second injection. The first step was to determine whether the time-concentration curve after the first injection was first-order. The second step was to calculate the concentration remaining after the first injection just before the second injection. The third step was to subtract the estimated residual after the first injection from the observed concentration at each time point after the second injection. The area under the curve (AUC) after the injection was calculated by adding two areas, the area from the injection to the last measured point according to the trapezoidal rule, and that from the last measured point to infinite time by extrapolation using the seven points before the final one. The clearance (CL) was obtained by dividing the dose by the AUC. The mean residence time (MRT) was calculated as the second moment of the time-concentration data. The volume of distribution (V ) was calculated by multiplying CL by MRT. Plasma clearance was converted to whole blood clearance using the haematocrit for each period of ICG injection. The extraction ratio was calculated as 1 minus the quotient of the AUCs.
Pharmacokinetic parameter data were statistically analyzed using ANOVA with Scheffe’s F-test.
Filed under: Clinical Pharmacology