Disposition and pharmacology of propofol glucuronide administered intravenously to animals

Abstract

1. Propofol glucuronide (PG) is the major human metabolite of the i.v. anaesthetic propofol, 2,6-diisopropylphenol. 2. Bolus i.v. doses of 14C-PG (1 mg/kg) to rat and dog were eliminated in urine (40 and 66% respectively) and faeces (48 and 19%); 25 and 48% of the dose were excreted unchanged in urine. 3. In dog, PG was distributed from plasma (t 1/2 4 min) into a volume equivalent to extracellular water and eliminated with t 1/2 80 min. Total body clearance was 1.8 ml/min per kg, and renal clearance about 20% GFR. In rat, plasma 14C concentrations were about one-tenth those in dog, thus PG levels were not quantified. 4. Propofol was not detected in the plasma showing that PG is hydrolytically stable. Enterohepatic circulation of PG occurred in rat and to a lesser extent in dog. Metabolites, mainly side-chain hydroxylation products, were evident in both species from 4 h after dosing. 5. Bolus i.v. doses of PG (200 mg/kg) showed no hypnotic activity in mice.

Identification and characterization of two chloramphenicol glucuronides from thein vitroglucuronidation of chloramphenicol in human liver microsomes

“…However, there were significant differences in the rate of formation of CP major glucuronide (3-O-CPGlu) between HLM and the liver microsomes from other species. The difference in the rate of glucuronidation has been observed previously in dog and human (Simons et al 1992). These differences in liver microsome glucuronidation between human and other species highlight the importance of in vitro experiments using human enzymes.…”

Pharmacokinetics and pharmacodynamics of propofol with or without 2% benzyl alcohol following a single induction dose administered intravenously in cats

“…As hepatic metabolism is necessary for the biotransformation and elimination of both drugs (Simons et al. , ), administration of the two drugs together can be expected to slow elimination and increase plasma drug concentrations (Perry et al. ), altering the pharmacokinetics of both agents.…”

“…Cats have decreased activity compared to other species studied in the glucuronidation pathways that are likely necessary for adequate metabolism of both propofol and benzyl alcohol (Bridges et al 1970;Bedford & Clarke 1972;Cullison et al 1983). As hepatic metabolism is necessary for the biotransformation and elimination of both drugs (Simons et al 1991(Simons et al , 1992, administration of the two drugs together can be expected to slow elimination and increase plasma drug concentrations (Perry et al 1991), altering the pharmacokinetics of both agents. There are several reports of benzyl alcohol toxicity in cats due to administration of substances containing this preservative (Bedford & Clarke 1971, 1972Humphreys 1976;Cullison et al 1983).…”

Opisthotonos following propofol: A nonepileptic perspective and treatment strategy

“…5,t' A glucuronide conjugate is the major, long-lasting metabolite of propofol in humans. 29 Unlike morphine glucuronides, propofol glueuronide is apparently inactive.…”