Prediction of total propofol clearance based on enzyme activities in microsomes from human kidney and liver.
OBJECTIVE
Propofol is commonly used for anesthesia and sedation in intensive care units. Approximately 53% of injected propofol is excreted in the urine as the glucuronide and 38% as hydroxylated metabolites. Liver, kidneys and intestine are suspected as clearance tissues. We investigated the contribution of the liver and kidneys to propofol metabolism in humans using an in vitro-in vivo scale up approach.


METHODS
Renal tissue was obtained from five patients who received nephrectomies. Each renal hydroxylation and glucuronidation enzymatic activities in microsomal fractions from patients were performed discretely and their estimation based on the decrease of propofol concentration. Hepatic hydroxylation and glucuronidation activities were also performed separately using human liver microsomes. This estimation is based on the decrease of propofol concentration, assuming that the contribution of hydroxylation activity without NADPH-generating system and glucuronidation activity without UDPGA in each microsomal fraction are negligible. Both renal and hepatic clearances were estimated assuming a well-stirred model.


RESULTS
Enzymatic activity of propofol oxidation in renal microsomes was negligible. Although glucuronidation activity in microsomes from kidneys was comparable to that from liver, the hepatic intrinsic clearance predicted from in vitro study was higher than that in kidneys due to the larger tissue volume and higher protein concentration. However, glucuronidation clearance in kidney is relatively similar to that in liver because of blood flow limitation of clearance in both tissues.


CONCLUSIONS
The high degree of hydroxylation activity in liver microsomes is consistent with the blood flow-limited hepatic clearance of propofol. Although the activity of propofol glucuronidation in liver is higher, glucuronidation in kidney may be a substantial contributor.
Al-Jahdari
Wael S
WS
Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
Yamamoto
Koujirou
K
Hiraoka
Haruhiko
H
Nakamura
Katsunori
K
Goto
Fumio
F
Horiuchi
Ryuya
R
D000368:Aged; D000369:Aged, 80 and over; D018686:Anesthetics, Intravenous / Q000494:pharmacology; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology*; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D008861:Microsomes / Q000187:drug effects* / Q000201:enzymology*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology*; D008875:Middle Aged; D015742:Propofol / Q000494:pharmacology*
D018686:Anesthetics, Intravenous; D020719:Glucuronides; D015742:Propofol