Comparison of rat dopamine D2 receptor occupancy for a series of antipsychotic drugs measured using radiolabeled or nonlabeled raclopride tracer

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156

This review discusses strategies to optimize brain penetration from the perspective of drug discovery and development. Brain penetration kinetics can be described by the extent and time to reach brain equilibrium. The extent is defined as the ratio of free brain concentration to free plasma concentration at steady state. For all central nervous system (CNS) drug discovery programs, optimization of the extent of brain penetration should focus on designing and selecting compounds having low efflux transport at the blood-brain barrier (BBB). The time to reach brain equilibrium is determined by both BBB permeability and brain tissue binding. Rapid brain penetration can be achieved by increasing passive permeability and reducing brain tissue binding. Although many drug transporters have been identified at the BBB, the available literature demonstrates only the in vivo functional importance of P-glycoprotein (P-gp) in limiting brain penetration of its substrates. Drug-drug interactions mediated by P-gp at the BBB are possible due to inhibition or induction of P-gp. For newly identified drug transporters at the BBB, more research is needed to reveal their in vivo significance. We propose the following strategies for addressing drug transporters at the BBB. 1) Drug discovery screens should be used to eliminate good P-gp substrates for CNS targets. Special consideration could be given to moderate P-gp substrates as potential CNS drugs based on a high unmet medical need and the presence of a large safety margin. 2) Selection of P-gp substrates as drug candidates for non-CNS targets can reduce their CNS-mediated side effects.Brain is separated from the systemic circulation by two barriers: the blood-brain barrier (BBB) and the blood-cerebrospinal-fluid barrier (BCSFB). The BBB is composed of cerebral endothelial cells that differ from those in the rest of the body by the presence of extensive tight junctions, absence of fenestrations, and sparse pinocytotic vesicular transport. The BCSFB is formed by a continuous layer of polarized epithelial cells that line the choroid plexus. The BBB and BCSFB exhibit very low paracellular permeability and express multiple drug transporters. These characteristics restrict the entry of hydrophilic compounds or efflux transport substrates into brain (Davson and Segal, 1995). In this review, we will summarize recent published data relevant to assess drug brain penetration and present the authors' opinions on how to effectively address BBB issues in drug discovery and development.

Section: Considerations Of the Methods Used To Study Brain Penetrationmentioning

confidence: 99%

Progress in Brain Penetration Evaluation in Drug Discovery and Development

Liu¹,

Chen²,

Smith³

2008

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156

“…Furthermore, for both HAL and ZIP, the doses selected (see below) would be expected to achieve comparable (and therapeutically) relevant D 2 receptor occupancy values in vivo (i.e., in the range 65-80%; see Kapur et al, 2003) based on the recent work of Barth et al (2006). Rats were thus treated with 2.0 mg/kg/day HAL (SigmaAldrich, St. Louis, MO) or 12.0 mg/kg/day ZIP (Pfizer, Inc., New York, NY) orally for periods of 7, 14, 45, or 90 days.…”

Section: Drug Dosing For Chronic Antipsychotic Experimentsmentioning

confidence: 99%

Time-Dependent Effects of Haloperidol and Ziprasidone on Nerve Growth Factor, Cholinergic Neurons, and Spatial Learning in Rats

Terry¹,

Parikh²,

Gearhart³

et al. 2006

In this rodent study, we evaluated the effects of different time periods (7, 14, 45, and 90 days) of oral treatment with haloperidol (HAL; 2.0 mg/kg/day) or ziprasidone (ZIP; 12.0 mg/kg/day) on nerve growth factor (NGF) and choline acetyltransferase (ChAT) levels in the hippocampus, and we subsequently assessed water maze task performance, prepulse inhibition (PPI) of the auditory gating response, and several NGF-related proteins and cholinergic markers after 90 days of treatment. Seven and 14 days of treatment with either HAL or ZIP resulted in a notable increase in NGF and ChAT immunoreactivity in the dentate gyrus (DG), CA1, and CA3 areas of the hippocampus. After 45 days, NGF and ChAT immunoreactivity had abated to control levels in ZIP-treated animals, but it was markedly reduced in HAL-treated subjects. After 90 days of treatment, NGF and ChAT levels were substantially lower than controls in both antipsychotic groups. Furthermore, after 90 days of treatment and a drug-free washout period, water maze performance (but not PPI) was impaired in both antipsychotic groups, although the decrement was greater in the HAL group. Several NGFrelated and cholinergic proteins were diminished in the brains of subjects treated with either neuroleptic as well. These data support the premise that, although ZIP (given chronically) seems somewhat superior to HAL due to less pronounced behavioral effects and a more delayed appearance of neurochemical deficits, both antipsychotics produce time-dependent deleterious effects on NGF, cholinergic markers (i.e., important neurobiological substrates of memory), and cognitive function.The newer pharmacological treatments for schizophrenia, now commonly referred to as second generation antipsychotics (SGAs), offer several advantages over first generation antipsychotics (FGAs) such as greater improvements in negative symptoms, prevention of relapse, increased functional capacity and quality of life, and fewer movement-related side effects (for review, see Miyamoto et al., 2005). It is also generally believed that SGAs are superior to FGAs when their effects on cognition are considered (for reviews, see Keefe et al., 1999;Purdon, 1999), and some studies suggest that SGAs improve cognition in schizophrenia. This suggestion is of particular importance given that the degree of cognitive impairment in schizophrenia is recognized as an important predictor of social functioning, unemployment, and even relapse of psychiatric symptoms (for review, see Castner et al., 2004). It should be noted, however, that such conclusions regarding antipsychotics and cognitive function rely primarily on meta-analyses and short clinical trials (i.e., they rarely exceed a few months to 1 year in length). There-

“…Furthermore, for both haloperidol and risperidone, the doses selected (see subsequent discussion) would be expected to achieve comparable (and therapeutically) relevant dopamine D2 receptor occupancy values in vivo (i.e., in the range 65-80%; see Kapur et al, 2003) based on the work of (Barth et al, 2006). Thus, rats were treated with 1.0 or 2.0 mg/kg daily of haloperidol (4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-1-(4-fluorophenyl)-butan-1-one; Sigma-Aldrich, St. Louis, MO) or 1.25 or 2.5 mg/kg daily of risperidone (4-[2-[4-(6-…”

Section: Drug Administrationmentioning

confidence: 99%

Differential Long-Term Effects of Haloperidol and Risperidone on the Acquisition and Performance of Tasks of Spatial Working and Short-Term Memory and Sustained Attention in Rats

Hutchings

Waller

Terry

2013

A common feature of the neuropsychiatric disorders for which antipsychotic drugs are prescribed is cognitive dysfunction, yet the effects of long-term antipsychotic treatment on cognition are largely unknown. In the current study, we evaluated the effects of long-term oral treatment with the first-generation antipsychotic haloperidol (1.0 and 2.0 mg/kg daily) and the secondgeneration antipsychotic risperidone (1.25 and 2.5 mg/kg daily) on the acquisition and performance of two radial-arm maze (RAM) tasks and a five-choice serial reaction-time task (5C-SRTT) in rats during days 15-60 and 84-320 days of treatment, respectively. In the RAM, neither antipsychotic significantly affected the acquisition or performance of a spatial win shift or a delayed non-match-to-position task. Conversely, in the rats administered 5C-SRTT, haloperidol was associated with profound deficits in performance, and the subjects were not able to progress through all stages of task acquisition. Depending on the dose, risperidone was associated with a greater number of trials to meet specific performance criteria during task acquisition compared with vehicle-treated controls; however, most subjects were eventually able to achieve all levels of task acquisition. Both haloperidol and risperidone also increased the number of perseverative and time-out responses during certain stages of task acquisition, and the response and reward latencies were slightly higher than controls during several stages of the study. These results in rats suggest that while long-term treatment with haloperidol or risperidone may not significantly affect spatial working or short-term memory, both antipsychotics can (depending on dose) impair sustained attention, decrease psychomotor speed, increase compulsivetype behaviors, and impair cognitive flexibility.