Pharmacokinetics of Haloperidol Decanoate in Rats.

Oh-E, Yoshinori; Miyazaki, Hisashi; Matsunaga, Yoshimasa; Hashimoto, Masahisa

doi:10.1248/bpb1978.14.615

Cited by 12 publications

(6 citation statements)

References 5 publications

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“…The rapid hydrolysis of the decanoate ester by blood esterase has been suggested in vivo 15 and the plasma concentration of haloperidol is reported to be lower than that in lymph 16 . In this regard, it is known that haloperidol decanoate can also be partially absorbed via the lymphatic system 17 . These results suggest that the limiting factor is not only the rate of diffusion of the esterified neuroleptic from the oil vehicle but also the rate of hydrolysis of haloperidol decanoate in the lymphatic system.…”

Section: Discussionmentioning

confidence: 93%

¹⁹F‐magnetic resonance spectroscopy and chemical shift imaging for schizophrenic patients using haloperidol decanoate

Sassa¹,

Suhara²,

Ikehira³

et al. 2002

Psychiatry Clin Neurosci

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Haloperidol decanoate is widely used in the maintenance treatment of schizophrenia and other psychotic disorders, but knowledge concerning its pharmacokinetics at the injected region is very limited. Because the chemical structure of haloperidol contains fluorine, in vivo 19F-magnetic resonance (MR) spectroscopy (repetition time (TR) = 1 s) and chemical shift imaging (CSI; TR = 1 s, pixel size = 15 x 15 mm) were performed in schizophrenic patients who were treated with haloperidol decanoate (three men and one woman) to measure its diachronic change at the injection point and visualize its local distribution after intramuscular injection. 19F signals (T1 time = 365 ms) were obtained at the haloperidol decanoate-injected region. The decrease rate of the signal-to-noise ratio (SNR) by 19F-MR spectroscopy seemed large in comparison with that of the plasma haloperidol concentration. The distribution was clearly visualized by 19F-CSI for a few days after the injection, but after 1 week could no longer be seen. Although the slow-release characteristics of depot neuroleptics have been explained by the slow diffusion of esterified neuroleptics from the oil vehicle, this result may suggest that there are other mechanisms involved in maintaining the plasma haloperidol concentration. In vivo 19F-MR spectroscopy and CSI are potentially applicable for the pharmacokinetic analysis of haloperidol and other drugs containing fluorine in their structure.

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Section: Discussionmentioning

confidence: 93%

¹⁹F‐magnetic resonance spectroscopy and chemical shift imaging for schizophrenic patients using haloperidol decanoate

Sassa¹,

Suhara²,

Ikehira³

et al. 2002

Psychiatry Clin Neurosci

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“…In the present study, injection volumes varied due to the dose of the drug and the concentration of the drug in the oil. It was generally considered that injections that use larger volumes may be better than smaller volumes as absorption of the decanoates from the oil vehicle is thought to be a rate-limiting factor for the long-lasting effects of these compounds [Dreyfuss et al, 1976;Matsunaga et al, 1987;Oh-E et al, 1991;Luo et al, 1997]. Whether this interpretation had any bearing on the results obtained is unclear, as experiments investigating the effect of injection volume on the activity of these type of drugs are, as yet, unavailable.…”

Section: Discussionmentioning

confidence: 99%

Effects of depot drug formulations in procedures used to evaluate antipsychotic activity in rodents

et al. 1999

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The use of long‐acting depot antipsychotics results in an increase in compliance and significantly decreases rates of relapse and rehospitalization of schizophrenic patients. However, the assessment of activity of such drugs in small animals is not as straightforward as the evaluation of acutely active drugs. Previous studies have investigated the effects of depot formulations by assessing their activity in preclinical methods that examine their striatal dopaminergic components alone. These methods are currently used to examine the extrapyramidal side‐effects of antipsychotic agents. In the light of recent drug developments, however, it is possible that such procedures may no longer be appropriate for testing antipsychotics which produce fewer side effects and which have a broader range of action including nondopaminergic components. Accordingly, the present study aimed to further investigate the activities of clinically used depot antipsychotics by using procedures that are considered more predictive of antipsychotic activity rather than extrapyramidal side‐effect liability. Along with acutely active analogs, flupenthixol decanoate, fluphenazine decanoate, and haloperidol decanoate were examined in the following procedures with rats or mice: antagonism of 1[2,5‐dimethoxy‐4‐iodophenyl]‐2‐aminopropane (DOI) ‐induced behaviors and amphetamine‐stimulated locomotion. Effects of the depot formulations in both procedures were determined at time points ranging from 24 h to 14 days after administration. In general, some antipsychotic‐related effects were observed with the drugs particularly at earlier time points; effects at 14 days were minimal. The results from this study demonstrate that depot formulations of antipsychotic drugs have effects in rodents, but factors possibly related to injection volume, test procedure, and species could limit the duration of action in small laboratory animals. Drug Dev. Res. 47:27–36, 1999. © 1999 Wiley‐Liss, Inc.

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“…The charged species are amphiphilic, having long fatty tails, and could reasonably be expected to have an influence on the properties of the sesame oil and its interaction with water, though no data have been published. Regardless of the mechanism of release from the oil, Oh-E, et al demonstrated that HAL-C10 is primarily absorbed into the lymphatic system and that the ester is most likely cleaved by esterases within lymphocytes …”

Section: Delivery Technologiesmentioning

confidence: 99%

Making the Leap from Daily Oral Dosing to Long-Acting Injectables: Lessons from the Antipsychotics

Remenar

2014

Mol. Pharmaceutics

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There are now long-acting versions of six antipsychotic drugs on the U.S. market, and with them, five unique combinations of molecular form and delivery strategy long-acting-injectable-antipsychotics (LAIAs) show evidence of reduced relapses of schizophrenia, but their introduction has been slow, taking at least nine years after the approval of each oral drug. Oily solutions of lipophilic prodrugs were the first to enter the LAIA market, but they relied on esterification of a hydroxyl handle that was lost with the emergence of the atypical antipsychotics. A review of the literature and patents shows that companies tested many different approaches before reaching the currently marketed versions, including aqueous suspensions of poorly soluble salts, polymeric microspheres, and new approaches to making prodrugs. Yet, very little has been published to support faster development of safe long-acting injectables (LAIs). This review introduces some of the critical considerations in creating an LAI; then it analyzes the existing products and discusses areas where further research is needed. The available literature suggests that lipophilic prodrugs may be inherently safer than poorly soluble salts as LAIs. Other areas needing additional study include (1) the range of physical properties acceptable for LAIs and the effect of prodrug tail length in achieving them, and (2) the role of physiological responses at the injection site in the release of drug from a depot.

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Pharmacokinetics of Haloperidol Decanoate in Rats.

Cited by 12 publications

References 5 publications

¹⁹F‐magnetic resonance spectroscopy and chemical shift imaging for schizophrenic patients using haloperidol decanoate

¹⁹F‐magnetic resonance spectroscopy and chemical shift imaging for schizophrenic patients using haloperidol decanoate

Effects of depot drug formulations in procedures used to evaluate antipsychotic activity in rodents

Making the Leap from Daily Oral Dosing to Long-Acting Injectables: Lessons from the Antipsychotics

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Pharmacokinetics of Haloperidol Decanoate in Rats.

Cited by 12 publications

References 5 publications

19F‐magnetic resonance spectroscopy and chemical shift imaging for schizophrenic patients using haloperidol decanoate

19F‐magnetic resonance spectroscopy and chemical shift imaging for schizophrenic patients using haloperidol decanoate

Effects of depot drug formulations in procedures used to evaluate antipsychotic activity in rodents

Making the Leap from Daily Oral Dosing to Long-Acting Injectables: Lessons from the Antipsychotics

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Product

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¹⁹F‐magnetic resonance spectroscopy and chemical shift imaging for schizophrenic patients using haloperidol decanoate

¹⁹F‐magnetic resonance spectroscopy and chemical shift imaging for schizophrenic patients using haloperidol decanoate