Drug metabolism letters · 2012
Renal and hepatic kinetics of Tc-99m-labelled hexakis-methoxy-isobutyl Isonitrile.
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Dizdarevic Sabina, Aplin Mark, Ryan Nicola, Holt Stephen G, Goldberg Lawrence, Miles Kenneth A, Peters A Michael
Аннотация
OBJECTIVE: Technetium-99m-labelled hexakis-methoxy-isobutyl isonitrile (Tc-99m-MIBI) is a substrate for P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter protein, and can be used to image P-gp expression. The aim was to study normal kinetics of Tc-99m-MIBI in the kidney and liver to help understand physiological studies of P-gp expression in these organs.
METHODS: Thirty healthy kidney transplant donors received intravenous Tc-99m-MIBI followed by dynamic scintigraphy for 20 min and static imaging at 30 and 120 min. Time-activity curves were generated from parenchymal ROI. An assumed mono-exponential Tc-99m-MIBI blood clearance with rate constant of 0.3 min-1 was used to predict the Tc-99m- MIBI that would have accumulated in the organs had none left. The activities leaving were then calculated by subtraction and expressed as percentages of the predicted total accumulated activities.
RESULTS: Kidney time-activity curves peaked at 2-4 min then declined to a plateau from ~15-16 min equal to 31 [SD 5]% of the total activity accumulated (corresponding to 69 [5]% rapidly eliminated) (phase 1). Bladder activity followed a similar but opposite time course. Between 30 and 120 min (phase 2), activity left at 0.36 (0.13) %.min-1. Liver curves peaked at 8-10 min. Differentiation of the elimination curve revealed that a variable proportion of tracer (5-56%; mean 30 [14]%) was rapidly excreted over ~11 min. From 30 min, activity left at 1.02 (0.23) %.min-1. There was no correlation between renal and hepatic elimination rates in either phase or between early and late phase elimination rates in either organ.
CONCLUSIONS: Early renal elimination is predominantly via glomerular filtration and urinary excretion. The liver rapidly excretes a more variable and lower proportion of Tc-99m-MIBI than the kidney. P-gp located at the urine/tubule and bile/hepatocyte boundaries prevents Tc-99m-MIBI re-entering cells and thereby influences elimination and retention in both phases, although other ABC transporters are probably also involved.
METHODS: Thirty healthy kidney transplant donors received intravenous Tc-99m-MIBI followed by dynamic scintigraphy for 20 min and static imaging at 30 and 120 min. Time-activity curves were generated from parenchymal ROI. An assumed mono-exponential Tc-99m-MIBI blood clearance with rate constant of 0.3 min-1 was used to predict the Tc-99m- MIBI that would have accumulated in the organs had none left. The activities leaving were then calculated by subtraction and expressed as percentages of the predicted total accumulated activities.
RESULTS: Kidney time-activity curves peaked at 2-4 min then declined to a plateau from ~15-16 min equal to 31 [SD 5]% of the total activity accumulated (corresponding to 69 [5]% rapidly eliminated) (phase 1). Bladder activity followed a similar but opposite time course. Between 30 and 120 min (phase 2), activity left at 0.36 (0.13) %.min-1. Liver curves peaked at 8-10 min. Differentiation of the elimination curve revealed that a variable proportion of tracer (5-56%; mean 30 [14]%) was rapidly excreted over ~11 min. From 30 min, activity left at 1.02 (0.23) %.min-1. There was no correlation between renal and hepatic elimination rates in either phase or between early and late phase elimination rates in either organ.
CONCLUSIONS: Early renal elimination is predominantly via glomerular filtration and urinary excretion. The liver rapidly excretes a more variable and lower proportion of Tc-99m-MIBI than the kidney. P-gp located at the urine/tubule and bile/hepatocyte boundaries prevents Tc-99m-MIBI re-entering cells and thereby influences elimination and retention in both phases, although other ABC transporters are probably also involved.