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

Seiler, Walther; Wetzel, Hermann; Hillert, Andreas; Schöllnhammer, G; Langer, Michael; Barlage, Uwe; Hiemke, Christoph

doi:10.1007/bf02247478

Cited by 7 publications

(3 citation statements)

References 19 publications

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“…They tend to be exclusively metabolized via N-dealkylation. 13,13b Likewise, the N-dealkylation is a major pathway for pimozide metabolism. 14 Similarly, domperidone is mainly metabolized by the N-dealkylation, with its hydroxylated metabolites at the benzimidazolone ring also observed.…”

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confidence: 99%

“…Take timiperone and benperidol, both of which are the butyrophenone class antipsychotic drugs for the treatment of schizophrenia. They tend to be exclusively metabolized via N-dealkylation. , Likewise, the N-dealkylation is a major pathway for pimozide metabolism . Similarly, domperidone is mainly metabolized by the N-dealkylation, with its hydroxylated metabolites at the benzimidazolone ring also observed .…”

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confidence: 99%

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Metabolism of 4-Aminopiperidine Drugs by Cytochrome P450s: Molecular and Quantum Mechanical Insights into Drug Design

Sun

Scott

2011

ACS Med. Chem. Lett.

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4-Aminopiperidines are a variety of therapeutic agents that are extensively metabolized by cytochrome P450s with CYP3A4 as a major isoform catalyzing their N-dealkylation reaction. However, its catalytic mechanism has not been fully elucidated in a molecular interaction level. Here, we applied theoretical approaches including the molecular mechanics-based docking to study the binding patterns and quantum mechanics-based reactivity calculations. They were supported by the experimental human liver microsomal clearance and P450 isoform phenotyping data. Our results herein suggested that the molecular interactions between substrates and CYP3A4 active site residues are essential for the N-dealkylation of 4-aminopiperidines. We also found that the serine 119 residue of CYP3A4 may serve as a key hydrogen-bonding partner to interact with the 4-amino groups of the studied drugs. The reactivity of the side chain α-carbon hydrogens drives the direction of catalysis as well. As a result, structure-based drug design approaches look promising to guide drug discovery programs into the optimized drug metabolism space.

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confidence: 99%

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Metabolism of 4-Aminopiperidine Drugs by Cytochrome P450s: Molecular and Quantum Mechanical Insights into Drug Design

Sun

Scott

2011

ACS Med. Chem. Lett.

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“…where (Seiler et al, 1994). Briefly, plasma samples with spiroperidol as internal standard were subjected to two-step solid phase extraction on reversed phase (C18) and strong cation exchange material.…”

Section: Determination Of Benperidolmentioning

confidence: 99%

Plasma levels of benperidol, prolactin, and homovanillic acid after intravenous versus two different kinds of oral application of the neuroleptic in schizophrenic patients

Seiler

Wetzel²,

Hillert³

et al. 2009

Exp Clin Endocrinol Diabetes

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Plasma levels of prolactin (PRL) and the butyrophenone neuroleptic benperidol (BPD) were closely followed 0 to 48 h after acute application of 6 mg BPD as intravenous injection, orally as liquid, and orally as tablets in 12 schizophrenic patients using a partially randomized cross over design. Drug concentrations showed application specific pharmacokinetic behavior with complete elimination within 48 h. All three applications led to a biphasic PRL response with pronounced initial plasma PRL peaks returning to baseline levels within 48 h. The results suggest that after acute neuroleptic challenge BPD plasma levels as low as 2-3 ng/ml can be sufficient for complete depletion of pituitary PRL stores. This initial peak was followed by a PRL plateau about twice above pretreatment values indicating doubling of the PRL synthesis and secretion independent of supraeffective actual BPD concentrations. The PRL plateau persisted as long as BPD concentrations were above those levels which triggered the initial PRL response. As compared with the time of maximum concentrations (tmax) for BPD, the PRL tmax was later after i.v. injection, equal after liquid application, and earlier after tablet administration leading to pronounced application specific differences in shape, direction, and position of resulting hysteresis curves. Plasma levels of homovanillic acid (HVA) were not affected by BPD treatment. The PRL and HVA levels registered after acute doses of BPD indicated that the hormone responses were most likely the result of acute depletion of PRL stores and subsequent stimulation of hormone synthesis whereas it seemed unlikely that dopaminergic activities were relevant.

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Benperidol for schizophrenia

Leucht

Hartung

2005

Cochrane Database of Systematic Reviews

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BackgroundBenperidol is a relatively old antipsychotic drug that has been marketed since 1966. It has been used in Germany for 30 years but is also available in Belgium, Greece, Italy, the Netherlands and the UK. Benperidol is a butyrophenone antipsychotic, with the highest neuroleptic potency in terms of D2 receptor blockade. Those taking it are therefore reputed to be at high risk of extrapyramidal side-e ects, but benperidol's unusual profile may render it valuable to certain subgroups of people with schizophrenia. ObjectivesTo examine the clinical e ects and safety of benperidol for those with schizophrenia and schizophrenia-like psychoses. Search methodsWe searched the Cochrane Schizophrenia Group's register (March 2009) for this update. Selection criteriaWe included all randomised controlled trials that compared benperidol with other treatments for people with schizophrenia, or schizophrenia-like psychoses. Data collection and analysisWe reliably selected studies, quality rated them and extracted data. We independently extracted data but excluded data if loss to follow up was greater than 50%. For dichotomous data, we estimated relative risks (RR), with the 95% confidence intervals (CI). Where possible, we calculated the number needed to treat/harm statistic (NNT/H) and used intention-to-treat analysis.Benperidol for schizophrenia (Review)

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

Cited by 7 publications

References 19 publications

Metabolism of 4-Aminopiperidine Drugs by Cytochrome P450s: Molecular and Quantum Mechanical Insights into Drug Design

Metabolism of 4-Aminopiperidine Drugs by Cytochrome P450s: Molecular and Quantum Mechanical Insights into Drug Design

Plasma levels of benperidol, prolactin, and homovanillic acid after intravenous versus two different kinds of oral application of the neuroleptic in schizophrenic patients

Benperidol for schizophrenia

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