Haloperidol metabolism in psychiatric patients: importance of glucuronidation and carbonyl reduction.
In 39 patients who received haloperidol regularly we measured plasma concentrations of haloperidol glucuronide (HAL-GL), reduced haloperidol glucuronide (RHAL-GL), haloperidol (HAL), reduced haloperidol (RHAL), and HAL reductase activity in red blood cells. Plasma HAL-GL concentrations were significantly higher than HAL, RHAL, or RHAL-GL concentrations. Concentration ratios of total glucuronide to nonglucuronide and RHAL/HAL ratios were calculated as indices of glucuronidation and reduction capacity in each patient. The plasma glucuronidation ratios showed a significant negative correlation (r = -0.63, p less than 0.001) with the dose, while the reduction ratios showed a positive correlation (r = 0.75, p less than 0.001). No correlations were found between the HAL reductase activity in red blood cells and either the dose or RHAL/HAL. Based on these findings we suggest that glucuronidation of HAL is the major metabolic pathway of HAL in humans and its activity is important in determining steady-state plasma HAL concentrations. Glucuronidation may also be a major contributing factor in the interindividual variability of HAL metabolism.
Someya
T
T
Department of Psychiatry, Shiga University of Medical Science, Otsu, Japan.
Shibasaki
M
M
Noguchi
T
T
Takahashi
S
S
Inaba
T
T
D000293:Adolescent; D000328:Adult; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D005965:Glucuronates / Q000378:metabolism; D006220:Haloperidol / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism*; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000378:metabolism*; D008875:Middle Aged; D010084:Oxidation-Reduction
D005965:Glucuronates; C040692:4-(4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl)-1-(4-fluorophenyl)-1-butanol; D000429:Alcohol Oxidoreductases; C063466:haloperidol reductase; D006220:Haloperidol