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Dear colleagues,
Has anyone information on risperidone, its active metabolite,
9-hydroxyrisperidone, and the clinical consequences of CYP2D6 inhibition.
In one article I read that 9-hydroxyrisperidone is metabolised further to an
inactive metabolite by oxidation and that 2D6 inhibitors like fluoxetine,
paroxetine and cometidine also may inhibit this second oxidation (1). Proper
references were missing.
Erik F.O. Pomp,
An ignorant DI-pharmacist
Regional Drug Information Centre
Bergen, Norway
Literature:
1) Cardoni A. Risperidone: Review and assessment of its role in the
treatment of schizophrenia. Ann Pharmacother 1995: 610-8.
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Hello Erik
Two articles on drug interactions of risperidone
Erythromycin interaction with risperidone or clomipramine in an adolescent
Fisman S, Reniers D, Diaz P
J Child Adolesc Psychopharmacol 1996;6(2):133-138
Pharmacokinetics and drug interactions: update for new antipsychotics.
Ereshefsky L
J Clin Psychiatry 1996;57 Suppl 11:12-25
Hope this helps
Chandrani Gunaratna
Chandrani Gunaratna, Ph.D.
Senior Research Chemist
Bioanalytical Systems
2701 Kent Avenue
West Lafayette, IN 47906
Phone: (765)463-4527
E-Mail: prema.aaa.bioanalytical.com
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Date: Tue, 25 Aug 1998 21:29:56 EDT
From: Vural Ozdemir
Reply-To: vural.ozdemir.-a-.utoronto.ca
Subject: Re: PharmPK Risperidone, 9-hydroxyrisperidone
To: PharmPK.at.pharm.cpb.uokhsc.edu
Priority: Normal
MIME-Version: 1.0
Dear Erik:
The metabolism of risperidone to 9-hydroxy risperidone is mediated by the
genetically polymorphic CYP2D6 enzyme (Huang et al. Clin Pharmacol Ther. 1993
Sep; 54(3): 257-268].
In vitro, this metabolite has comparable activity compared to that of
risperidone -
with respect to effects on the dopamine D2 receptor [see Huang et al.
1993].
In addition, this metabolite appears to cross the blood-brain-barrier
because the in
vivo D2 occupancy values overlap between the extensive (EM) and poor
metabolizers (PM) of CYP2D6 (see Nyberg et al. Psychopharmacology (Berl). 1995
Jun; 119(3): 345-348].
The sum of the active moieties (i.e. risperidone plus the 9-OH risperidone]
is also
similar between the EMs and PMs (Huang et al. 1993).
Therefore, these data would predict that the inhibition of CYP2D6 activity
by potent
inhibitors such as fluoxetine or paroxetine should have minimal clinical
consequences, at least with respect to the antidopaminergic side effects,
since the
increase in parent compound concentration would be counterbalanced by a
decrease in active metabolite levels. However, CYP2D6 inhibition may still
potentially lead to clinically significant side effects, when other
nondopaminergic
side effects are concerned.
I hope this information is useful.
With best regards,
Vural Ozdemir
Dept. of Pharmacology
University of Toronto
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X-Originating-IP: [194.95.249.3]
From: "Krishna Devarakonda"
To: PharmPK.aaa.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK Risperidone, 9-hydroxyrisperidone
Date: Wed, 26 Aug 1998 02:57:40 PDT
The following review article is quite useful:
D.R.Krishna,Ph.D
AvH Scientist
Dr.Margarete-Fischer-Bosch-Institue
of Clinical Pharmacology
Auerbachstr.112
70376 Stuttgart, Germany
---------
Clin Pharmacokinet 1997 Dec;33(6):454-471
Selective serotonin reuptake inhibitors and CNS drug interactions. A
critical review of the evidence.
Sproule BA, Naranjo CA, Brenmer KE, Hassan PC
Psychopharmacology Research Program, Sunnybrook Health Science Centre,
Toronto, Ontario, Canada.
The potential for drug-drug interactions in psychiatric patients is very
high as combination psychopharmacotherapy used to
treat comorbid psychiatric disorders, to treat the adverse effects of a
medication, to augment a medication effect or to treat
concomitant medical illnesses. Interactions can be pharmacodynamic or
pharmacokinetic in nature. This paper focuses on the
metabolic kinetic interactions between selective serotonin reuptake
inhibitors (SSRIs) and other central nervous system
(CNS) drugs. The evidence for and clinical significance of these
interactions are reviewed, with special emphasis on
antipsychotics, tricyclic antidepressants and benzodiazepines. Many
psychotropic medications have an affinity for the
cytochrome P450 (CYP) enzymes which promote elimination by transforming
lipid soluble substances into more polar
compounds. SSRIs serve both as substrates and inhibitors of these
enzymes. In vitro studies provide a screening method for
evaluating drug affinities for substrates, inhibitors or inducers of CYP
enzymes. Although in vitro data are important as a
starting point for predicting these metabolic kinetic drug interactions,
case reports and controlled experimental studies in
humans are required to fully evaluate their clinical significance.
Several factors must be considered when evaluating the clinical
significance of a potential interaction including: (a) the nature of
each drugs' activity at an enzyme site (substrate, inhibitor or
inducer); (b) the potency estimations for the inhibitor/inducer; (c) the
concentration of the inhibitor/inducer at the enzyme site;
(d) the saturability of the enzyme; (e) the extent of metabolism of the
substrate through this enzyme (versus alternative
metabolic routes); (f) the presence of active metabolites of the
substrate; (g) the therapeutic window of the substrate; (h) the
inherent enzyme activity of the individual, phenotyping/genotyping
information; (i) the level of risk of the individual
experiencing adverse effects (e.g. the elderly) and (j) from an
epidemiological perspective, the probability of concurrent use.
This paper systematically reviews both the in vitro and in vivo evidence
for drug interactions between SSRIs and other CNS
drugs. As potent inhibitors of CYP2D6, both paroxetine and fluoxetine
have the potential to increase the plasma
concentrations of antipsychotic medications metabolised through this
enzyme, including perphenazine, haloperidol, thioridazine
and risperidone in patients who are CYP2D6 extensive metabolisers.
Controlled studies have demonstrated this for
perphenazine with paroxetine and haloperidol with fluoxetine.
Fluvoxamine, as a potent inhibitor of CYP1A2, can inhibit the
metabolism of clozapine, resulting in higher plasma concentrations. Drug
interactions between the SSRIs and tricyclic
antidepressants (TCAs) can occur. Fluoxetine and paroxetine, as potent
inhibitors of CYP2D6, can increase the plasma
concentrations of secondary and tertiary tricyclic antidepressants.
Sertraline and citalopram are less likely to have this effect.
Fluvoxamine can increase the plasma concentrations of tertiary TCAs.
Fluvoxamine inhibits, via CYP3A. CYP2C19 and
CYP1A2, the metabolism of several benzodiazepines, including alprazolam,
bromazepam and diazepam. Fluoxetine increases
the plasma concentrations of alprazolam and diazepam by inhibiting CYP3A
and CYP2C19, respectively. The clinical
importance of the interaction with diazepam is attenuated by the
presence of its active metabolite. Sertraline inhibits these
enzymes only mildely to moderately at usual therapeutic doses. Therefore
the potential for interactions is less; however, the in
vivo evidence is minimal. Paroxetine and citalopram are unlikely to
cause interactions with benzodiazepines. The evidence is
conflicting for an interaction between carbamazepine and the SSRIs
fluoxetine and fluvoxamine. These combinations should
be used cautiously, and be accompanied by monitoring for adverse events
and carb
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[Three replies - db]
Date: Wed, 26 Aug 1998 15:51:51 -0400
From: Charles Grudzinskas
Subject: PharmPK Re: Risperidone, 9-hydroxyrisperidone
Sender: Charles Grudzinskas
To: "INTERNET:PharmPK.-at-.pharm.cpb.uokhsc.edu"
Cc: Multiple recipients of PharmPK - Sent by
MIME-Version: 1.0
I passed your e-mail re resperidone on to Dave Flockhart (Georgetown) who
had the following suggestions.
Charles Grudzinskas
Drug Development Consultant
cgrudzinskas.aaa.compuserve.com
410-255-5135
This primary reference might help. It deals with the 2D6 issue. The label
is also helpful
Huang,M.-L. et al: Pharmacokinetics of the Novel Antipsychotic Agent
Risperidone and the Prolactin Response in Healthy Subjects. Clin Pharmacol
Ther 54, 257-263, 1993.
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Date: Wed, 26 Aug 1998 11:37:06 +1000
From: "David A Flockhart MD, PhD"
MIME-Version: 1.0
To: Charles Grudzinskas
CC: PharmPK.at.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK Risperidone, 9-hydroxyrisperidone
This primary reference might help. It deals with the 2D6 issue, I beleive.
The label is also helpful.
Dave
Huang,M.-L. et al: Pharmacokinetics of the Novel Antipsychotic Agent
Risperidone and the Prolactin Response in Healthy Subjects. Clin Pharmacol
Ther 54, 257-263, 1993.
--
David A Flockhart MD, PhD
Assistant Professor of Medicine and Pharmacology
Director, Pharmacogenetics Core Laboratory
Division of Clinical Pharmacology
Georgetown University Medical Center
202-687-2882
202-687-0330 FAX
NEW E-mail: FLOCKHAD.-a-.medlib.georgetown.edu
---
From: Erik Fred Oscar Pomp
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
Subject: SV: PharmPK Re: Risperidone, 9-hydroxyrisperidone
Date: Thu, 27 Aug 1998 09:24:45 +0200
MIME-Version: 1.0
Hello dear responders,
Thank you so much for answering my questions. However, my question about the
further metabolism of the active metabolite 9-HO-risperidone remains
unanswered. One author is suggesting that three substances known as CYP2D6
inhibitors also may inhibit this further metabolism. This might lead one to
believe that risperidone is metabolised twice by the cytochrome P450 system.
Or is this a crazy thought? (With cometidine I mean cimetidine of course.)
Kind regards,
Erik
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Per Janssen (Belgium), they do not have the metabolic profile worked out
for 9-OH risperidone - but are looking at it now. I have been interested
in this recently as well with some case reports of drug interactions
between risperidone and carbamazepine (de Leon J & Bork J. J Clin
Psychiatry 1997;58:450 letter]. In this particular case report only 9-OH Cp
data is available and authors report significant increases in Cp 10 days
after CBZ discontinuation (Cp might be expected to increase even more if
measured > 10 days post CBZ discontinuation since induction effects will
persist for 2-4 weeks).
Cara L. Alfaro, Pharm.D., BCPP
Clinical Pharmacy Specialist for NIMH
NIH Clinical Center Pharmacy Department
Building 10, Room 1N-257
10 Center Drive
Bethesda, MD 20892
1-800 NIH BEEP (5267) [pager]
(301) 496-4363 [phone/voice mail]
(301) 496-0210 [fax]
PharmPK Discussion List Archive Index page
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