Linear pharmacokinetics of haloperidol in the rat

Abstract

Pharmacokinetics of haloperidol in the rat following intravenous bolus doses of 0.5, 1.0, and 2.5 mg kg-1, respectively, were investigated. It was found that haloperidol was a high extraction ratio drug with a total blood clearance averaging 83 ml min-1 kg-1. The volumes of distribution were large with a mean of 5.5 1 kg-1 (Vc), 11.11 kg-1 (V beta), and 9.61 kg-1 (Vss), respectively. The terminal half-life was 1.5 h. The disposition kinetics of haloperidol was found to be linear over the dose range studied. After constant intravenous infusions of haloperidol by different infusion rates during 12 h, steady-state levels were reached in the blood. The measured steady-state blood concentrations were consistent with those predicted by a biexponential infusion model based on the parameters obtained from the intravenous bolus study. The total blood clearance at steady-state was concentration-independent within the investigated range of 5 to 20 ng ml-1.

Chronic Antipsychotic Drug Treatment Induces Long-lasting Expression of fos and jun Family Genes and Activator Protein 1 Complex in the Rat Prefrontal Cortex

“…Therefore, it is unlikely that significant amounts of clozapine are present in brain 24 h or later after the cessation of chronic treatment. Similarly, haloperidol has been described to have a terminal half-life of 1.5 h in rat (Cheng and Paalzow 1992), but longer half-lives have also been reported . Consequently, residual amounts of haloperidol may still be present in brain after several days of drug withdrawal.…”

“Breakthrough” Dopamine Supersensitivity during Ongoing Antipsychotic Treatment Leads to Treatment Failure over Time

“…This is an important issue when one considers that the terminal half-life of haloperidol is 24 h in humans (Bezchlibnyk-Butler and Jeffries, 1999) and 1.5 h in rats (Cheng and Paalzow, 1992). Thus, 24 h after a single dose of haloperidol, D 2 occupancy levels remain high in humans (Farde et al, 1989;Seeman, 2002), but fall to well below clinically relevant levels in rats (Kapur et al, 2000a).…”

“…However, antipsychotics were given in the drinking water and plasma drug levels were not monitored. Rats consume up to 90% of their daily water intake during the dark phase (Stellar and Hill, 1952;Fitzsimons, 1957) and metabolize antipsychotics much faster than humans (Cheng and Paalzow, 1992;Bezchlibnyk-Butler and Jeffries, 1999); thus, the levels of antipsychotic exposure achieved by Clow et al (1979Clow et al ( , 1980 were unrepresentative of the clinical condition (Farde et al, 1989;Seeman, 2002).…”

Detection of the Moderately Beneficial Cognitive Effects of Low-Dose Treatment with Haloperidol or Clozapine in an Animal Model of the Attentional Impairments of Schizophrenia

“…Defining a low dose in terms of lower, 50% D2 receptor occupancy, 0.025 mg per kg (Li et al, 2007a) was selected as a dose (see also Table 1 in Kapur et al, 2003). Haloperidol was administered for 10 days and given 30 min prior to the task onset, so that performance was assessed while plasma levels rose and before reaching the half-life point for haloperidol in rats (Cheng and Paalzow, 1992). The selection of a low dose of clozapine (2.5 mg per kg) likewise followed the rationale suggested by Kapur et al (2003;see their Table 1).…”