An investigation of potential genetic determinants of propofol requirements and recovery from anaesthesia.
OBJECTIVE
The objectives of this study were, firstly, to characterize the inter-patient variability in the dose of propofol required to achieve a bispectral index <70 and 'time to eye opening' following propofol infusion and, secondly, to determine if the pharmacodynamic parameter 'time to achieve bispectral index <70' was influenced by genotype of the sex-linked drug receptor gene GABRE or if pharmacokinetic parameters such as clearance and 'time to eye opening' were influenced by the genotype of the metabolizing enzyme CYP2B6.


METHODS
One hundred and fifty patients received a standardized anaesthetic. Apparent systemic clearance values were estimated. Correlation was sought between carriers of different CYP2B6 and GABRE genotypes and apparent systemic clearance, 'time to achieve bispectral index <70' and 'time to eye opening'.


RESULTS
Propofol induction/emergence characteristics varied, with slow recovery times in a subset of males. Time to loss of verbal contact and time to bispectral index <70 varied 6.6- and 4.3-fold, respectively. At emergence, there was a 15.5- to 111-fold variability in the measured time intervals. Clearance varied from 9.1 to 55.8 mL min-1 kg-1. The CYP2B6 C1459T (R487C) genotype frequencies were TT 1%, TC 22% and CC 67%. The three major haplotypes of CYP2B6 (R487C, K262R and Q172H variants) were not significantly associated with time to eye opening or clearance. Clearance was similar in 487C carriers and 487RR genotypes. There was no statistically significant correlation between the four major haplotypes of GABRE variants investigated ([mRNA358]G/T, 20118C/T, 20326C/T and 20502 A/T) and the observed anaesthesia induction time.


CONCLUSIONS
Great inter-patient variability exists in the dose of propofol required to achieve bispectral index <70, apparent systemic propofol clearance and time to eye opening. Common haplotypic differences at the CYP2B6 and GABRE genes do not appear to account for the majority of the observed inter-patient variability.
Iohom
G
G
Beaumont Hospital, Department of Anaesthesia and Intensive Care Medicine, Dublin, Ireland. iohom@hotmail.com
Ni Chonghaile
M
M
O'Brien
J K
JK
Cunningham
A J
AJ
Fitzgerald
D F
DF
Shields
D C
DC
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000762:Anesthesia Recovery Period; D000771:Anesthesia, Intravenous; D018686:Anesthetics, Intravenous / Q000008:administration & dosage* / Q000097:blood; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics; D065702:Cytochrome P-450 CYP2B6; D004247:DNA / Q000235:genetics; D004569:Electroencephalography; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics; D015742:Propofol / Q000008:administration & dosage* / Q000097:blood; D011963:Receptors, GABA-A / Q000235:genetics
D018686:Anesthetics, Intravenous; C546274:GABRE protein, human; D011963:Receptors, GABA-A; D004247:DNA; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D015742:Propofol