Reversible metabolism of haloperidol and reduced haloperidol in Chinese schizophrenic patients

Abstract

Haloperidol disposition has been associated with reversible metabolism: it is reversibly reduced to its metabolite, reduced haloperidol, which has less pharmacologic activity than the parent compound. To characterize the interconversion process, six healthy male schizophrenics were administered a single dose of 10 mg haloperidol or reduced haloperidol in a randomized crossover manner. Using a general pharmacokinetic model for the interconversion process, the clearances of haloperidol and reduced haloperidol are 1.15 +/- 0.32 l/h/kg and 0.76 +/- 54 l/h/kg, respectively. These clearances are similar to that obtained by the usual mammillary model analysis. With a single 10 mg dose administration of either drug, about 23% of the biotransformation of haloperidol involves the reduction pathway. Back conversion from the reduced metabolite to the parent drug through oxidation contributes even less to the total biotransformation of reduced haloperidol. This action of interconversion or saturation under chronic drug administration is unknown. Reversible metabolism of haloperidol could partially account for the wide therapeutic range for haloperidol as reported in the literature.

The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment

“…18 Hepatic biotransformation includes glucuronidation (about 50%-60% in vivo) and reduction and back-oxidation (23%), as well as N-dealkylation and pyridinium metabolite formation (about 20%-30%). [19][20][21][22] The glucuronide metabolite is inactive, whereas reduced haloperidol has significant pharmacologic effects (eg, high-affinity binding to sigma-type opioid receptor-binding sites and to dopamine D 2 and D 3 receptors). 23 The concentrations of haloperidol and reduced haloperidol appeared to correlate with clinical response and adverse effects.…”

Pharmacokinetics and bioavailability of benperidol in schizophrenic patients after intravenous and two different kinds of oral application

“…Larsson et aI. 1983;Jann et al 1984). However, in a study with single oral doses of 5 mg haloperidol acutely, given to 29 healthy volunteers Midha et al (1989a) found reduced haloperidol in only six subjects with maximum plasma concentrations below 0.6 ng/ml.…”

The plasma haloperidol and reduced haloperidol concentrations in chinese schizophrenic patients: Relationship between reduced haloperidol/haloperidol ratio and red blood cell haloperidol reductase activity

“…As RHAL can be reconverted to HAL in vivo (Chakroborty et al, 1989;Jann et al, 1990), it formed a endogenous pool for HAL. Thus if RHAL is injected to patients, it will produce similar effects as HAL in changing the turnover of dopamine (Chang et al, 1989).…”

“…HAL is metabolised in liver by oxidative dealkylation to inactive metabolite and also by keto-reduction to RHAL (Forsman and Larsson, 1978). As RHAL can be reconverted to HAL in vivo (Chakroborty et al, 1989;Jann et al, 1990), it formed a endogenous pool for HAL. Thus if RHAL is injected to patients, it will produce similar effects as HAL in changing the turnover of dopamine (Chang et al, 1989).…”