Propofol clearance

Takizawa D, Sato E, Hiraoka H, et al. Changes in apparent systemic clearance of propofol during transplantation of living related donor liver. Br J Anaesth 2005 95 (5) 643-647. 

The two principal parenteral anesthetic drugs used clinically are thiopental (an old prototype) and propofol (a relatively new drug). Thiopental is a derivative of barbituric acid, while propofol is a substituted propylphenol. Onset and duration of anesthetic effect for the two drugs are similar. However, recovery is more rapid following infusion with propofol (a desirable feature). The relatively rapid clearance of propofol explains its less severe hangover in patients compared to thiopental and may allow for a more accelerated discharge from the recovery room. 

CYP2B6 is present at low level (< 1 %) in the liver. It catalyzes bupropion hydroxylation, S-mephenytoin N-demethylation, is involved in the metabolism of cyclophosphamide, ifosfamide, mianserin and propofol. CYP2B6 6 has been associated with reduced bupropion clearance in vitro (Hesse 2004), but not in vivo whereas a moderate clearance increase was observed with CYP2B6 4 (Kirchheiner 2003). Bupropion (150 mg dose) has been proposed for phenotyping, but it is recommended to adjust dose based on subject weight (Faucette 2000). 

Hamaoka N, Oda Y, Hase I, Mizutani K, Nakamoto T, Ishizaki T, Asada A. Propofol decreases the clearance of midazolam by inhibiting CYP3A4 an in vivo and in vitro study. Clin Pharmacol Ther 1999 66(2) 110-7. 

The systemic clearance of propofol, based on measurement of blood concentrations, in humans (31ml/ min X kg) and dogs (59 ml/min x kg) exceeds liver blood flow, which is 24 and 42ml/min per kilogram... 

In 21 critically ill children aged 1 week to 12 years, who were also receiving morphine by infusion, propofol kinetics were altered in very small babies and in children of all ages recovering from cardiac surgery (81). Increased volume of distribution and reduced metabolic clearance caused a prolonged half-life. The combination of morphine 20-40 micrograms/kg and 2% propofol 4-6 mg/kg/hour for up to 28 hours appears to be safe. 

In that study, propofol had an elimination half-life of 69 min in the horse, with a total body clearance of 33ml/kg/min. The principal site of elimination of propofol is the liver however, the clearance of propofol exceeds hepatic blood flow, suggesting an extrahepatic site of metabolism (Kuipers et al 1999). In dogs, propofol undergoes biotransformation to 4-hydroxypropofol by cytochrome P450 enzymes (Court et al 1999). 

Kuipers J A, Boer F, Olieman W et al 1999 First-pass lung uptake and pulmonary clearance of propofol assessment with a recirculatory indocyanine green pharmacokinetic model. Anesthesiology 91 1780-1787... 

Propofol is chiefly eliminated by hepatic conjugation to inactive metabolites, which are excreted by the kidney. A glucuronide conjugate accounts for about 50% of the administered dose. Following an IV bolus dose, plasma levels initially decline rapidly due to both high metabolic clearance and rapid drug distribution into tissues. Distribution accounts for about half of this decline following a bolus of propofol. 

The pharmacokinetics of propofol are summarized in Table 13-2. Propofol s duration q/ier infusion (shorter than that of thiopental) can be explained by its very high clearance, coupled with the slow diffusion of drug from the peripheral to the central compartment. The rapid clearance of propofol explains its less severe hangover compared with barbiturates and may allow for a more rapid discharge from the recovery room. Propofol is metabolized in the liver to less active metabolites that are renally excreted Propofol is highly protein bound, and its pharmacokinetics, like those of the barbiturates, may be affected by conditions that alter serum protein levels. 

Propofol Propofol produces anesthesia at a rate similar to that of the intravenous barbiturates, and recovery is more rapid. Propofol has antiemetic actions, and recovery is not delayed after prolonged infusion. The drug is commonly used as a component of balanced anesthesia and as an anesthetic in outpatient surgery. Propofol may cause marked hypotension during induction of anesthesia, primarily through decreased peripheral resistance. Total body clearance of propofol is greater than hepatic blood flow, suggesting that its elimination includes other mechanisms in addition to metabolism by liver enzymes. 

C. It is highly protein bound, with a volume of distribution of 2-5 L/kg after a single infusion, and 25-60 L/kg after a continuous infusion of greater than 7 days. Propofol has a high clearance rate estimated at 1.5-2.2 L/min. This clearance rate exceeds hepatic blood flow and suggests extrahepatic metabolism. 

A further double-blind, placebo-controlled study in 24 patients found that propofol decreased the clearance of midazolam by 37% and increased its elimination half-life by 61%. ... 

An in vitro study suggests that propofol may reduce the clearance of midazolam by inhibition of the cytochrome P450 isoenzyme CYP3A4. ... 

A study in 20 patients undergoing spinal anaesthesia with tetracaine found that propofol sedation (as measured by bispectral index monitoring (BIS)) was enhanced when adrenaline was added to the intrathecal tetracaine." A study in sheep found that adrenaline, noradrenaline and dopamine decreased propofol concentrations during a continuous propofol infusion, with the result that propofol anaesthesia was reversed. This was thought to be due to increased first pass clearance of propofol secondary to increased cardiac output. It was concluded that this could be of clinical importance if propofol is used in hyperdynamic circulatory conditions induced by either catecholamine infusions or disease states such as sepsis. ... 

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