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.2001 Jan;51(1):45-52.
doi: 10.1046/j.1365-2125.2001.01313.x.

Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition by reduced haloperidol

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Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition by reduced haloperidol

J G Shin et al. Br J Clin Pharmacol.2001 Jan.

Abstract

Aims: We evaluated the inhibitory effect of haloperidol and its metabolites on CYP2D6 activity in order to better understand the potential role of these metabolites in drug interactions involving haloperidol.

Methods: The inhibitory effects of haloperidol and five of its metabolites on dextrorphan formation from dextromethorphan, a marker probe of CYP2D6 activity, were measured in human liver microsomal preparations. Apparent kinetic parameters for enzyme inhibition were determined by nonlinear regression analysis of the data.

Results: Racemic reduced haloperidol and its metabolite, RHPTP competitively inhibited dextromethorphan O-demethylation with estimated Ki values (0.24 microM and 0.09 microM, respectively) that were substantially lower than that of haloperidol (0.89 microM). The inhibitory effect of S(-)-reduced haloperidol was more potent than the R(+)-enantiomer, with estimated Ki values of 0.11 microM and 1.1 microM, respectively. The pyridinium metabolite of haloperidol, HPP+ inhibited the enzyme activity noncompetitively with a Ki value of 0.79 microM. The N-dealkylated metabolites of haloperidol (FBPA and CPHP) had a diminished inhibitory potency. While FBPA showed no notable inhibitory effect on dextrorphan formation, CPHP showed moderate competitive inhibition with a Ki value of 20.9 microM.

Conclusions: The principal metabolites of haloperidol inhibit CYP2D6, suggesting that they might contribute to the inhibitory effects of the drug. Reduced haloperidol seems to inhibit CYP2D6 activity in an enantioselective manner with the physiologically occurring S(-) enantiomer being more potent.

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Figures

Figure 1
Figure 1
Metabolic pathways of haloperidol. Values in parentheses indicate the reference number. Solid arrows indicate the known metabolic pathways and dotted arrows metabolic pathways for which the enzymes involved have not been reported yet. HPTP and RHPTP are foundin vitro, but not detected inin vivo studies [44]. Abbreviations are: FBPA:p-fluorobenzoyl propionic acid, CPHP: 4-chlorophenyl-4-hydroxypiperidine, FBHP: 4-(p-fluorophenyl)-4-hydroxybutyric acid, HAL-GLU: haloperidol glucuronide, S(–)RHAL: S(–) reduced haloperidol enantiomer, RHAL-GLU: reduced haloperidol glucuronide, RHAL-SUL: reduced haloperidol sulphate, HPTP: 4-(4-(chlorophenyl)-1-[4-(fluorophenyl)-4-oxybutyl]-1,2,3 [, -tetrahydropyridine, HPP+: 4-(4-(chlorophenyl)-1-[4-(fluorophenyl)-4-oxybutyl]-pyridinium, RHPTP:: 4-(4-(chlorophenyl)-1-[4-(fluorophenyl)-4-hydroxybutyl]-1,2,3,6-tetrahydropyridine, RHPP + : 4-(4-(chlorophenyl)-1–4-(fluorophenyl)-4-hydroxybutyl-pyridinium: CR, carbonyl reductase.
Figure 2
Figure 2
Effect of haloperidol (•) and its metabolites (FBPA; ▴ CPHP; □ HPP+ ▾ RHPTP;rac-RHAL) on CYP2D6 catalysed dextromethorphanO-demethylation in human liver microsomes. Human liver microsomes were incubated with 25 µm dextromethorphan and haloperidol or its metabolites (0–50 µm) for 30 min. Each data point is the mean ± s.d. of the percent of control activity measured by the dextrorphan formation rate from three different liver microsomal preparations.
Figure 3
Figure 3
Dixon plots showing the inhibition of CYP2D6 catalysed dextromethorphanO-demethylation by haloperidol and its metabolites. Except for FBPA (b) and CPHP (c), Dixon plots of other haloperidol/metabolites showed nonlinear relationships. Human liver microsomes (HL-10) were incubated with 10 (•), 25 (♦), 50 (▴), and 75 µm (▾) dextromethorphan and haloperidol/metabolites (0–50 µm) for 30 min.
Figure 4
Figure 4
Representative nonlinear regression fit of dextrorphan formation ratevs dextromethorphan (10–75 µm). Each symbol and solid line indicates the observed and predicted dextrorphan formation rate in the absence (•) and presence of reduced haloperidol 0.5 (○), 1 (▪), 5 (□), 10 (▴), 25 (▵) and 50 µm (♦), respectively. The inhibition of dextrorphan formation by reduced haloperidol was best described by a partial competitive inhibition model [30] with the following parameter estimates:Vmax 0.49 nmol min−1 mg−1 protein,Km 25.09 µm,Ki 0.19 µm and α 1 7.2.
Figure 5
Figure 5
Comparison of inhibition of CYP2D6 catalysed dextromethorphanO-demethylation byrac-reduced haloperidol (open columns) with S(–) (closed columns) and R(+) (shaded columns) reduced haloperidol enantiomers. Human liver microsomes were incubated with 25 µm dextromethorphan andrac-reduced haloperidol or S(–) or R(+)-reduced haloperidol enantiomer (0–50 µm) for 30 min. Each data point is the mean ± s.d. percent remaining activity after exposure to each inhibitor with three different liver microsomal preparations.
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