Clozapine-associated pancreatitis and the CYP1A2*1F/1F genotype
Summary
A 40-yr.-old woman with paranoid schizophrenia developed asymptomatic
pancreatitis without eosinophilia one month after receiving clozapine, slowly increased to 300
mg/day. She had elevated serum levels of clozapine and hyperglycemia, but not hyperlipidemia.
She improved after discontinuation and recovered in about ten days. After a subsequent rechallenge
with 100 mg clozapine, she redeveloped pancreatitis associated with clozapine serum level
elevation. Clozapine was definitively discontinued, and this was followed by resolution of
pancreatic symptoms. Pharmacogenomic analysis of her CYP 1A2 isoenzyme showed her to
possess the *1F/1F genotype and the 3A4*1A/1A wildtype allelic variant. Pharmacogenomic data
may not match those of therapeutic drug monitoring. We would have expected high clozapine levels
to result from particular CYP 1A2 or 3A4 alleles that confer the status of poor metabolizer, but this
was not so.
Background Pancreatitis during treatment with classical neuroleptics is rarely reported; its
relationship to a specific antipsychotic has not been established1A. The risk for hospitalization for
acute pancreatitis was higher in patients receiving low-potency phenothiazines in a Danish
population, even adjusting for presence of diabetes, gallstones, alcohol-related disease, or use of
antidepressants, statins, or nonsteroidal anti-inflammatory drugs2A, but these figures were not
correcting for market share. After the introduction of second-generation antipsychotics, the
frequency of reports of pancreatitis in the course of antipsychotic treatment rose steeply3A. The
reason for this is not clear, as the newer antipsychotics are chemically heterogeneous, but so were
also the classical antipsychotics.
Pancreatitis is suspected to result from drug-induced hyperlipidaemia4A. Clozapine and other newer
antipsychotics have been linked hyperlipidemia and hyperglycemia5A, but a dose- or plasma levelrelated elevation of these measures is still not established.
Rating scales. Psychopathology. We used the 24-item, expanded Brief Psychiatric Rating Scale
(BPRS)6A (range, 24-168) to rate psychosis.
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Clozapine-associated pancreatitis and the CYP1A2*1F/1F genotype
Attribution of side effect and classification. We rated the likelihood that the side effect was due to
clozapine on the Naranjo ADR Probability Scale7A and obtained a score of 9, which is compatible
with high probability. Following Cerulli’s et al.4A subdivision into definite, probable, and possible
association, we found the event to be definitively associated with the use of clozapine.
Antibiotic treatment. We added intravenous ciprofloxacin, 400 mg/day for 14 days, according to
current guidelines for acute pancreatitis with acute phase reaction8A. This drug could interfere with
residual clozapine levels, elevating them9A,10A,11A.
Wash-out.
Wash-out is indicated when using drugs like risperidone, because this drug may
elevate plasma clozapine levels9A.
Pharmacogenomics. Genomic DNA was isolated from peripheral blood using the X-tractor Gene
system (Corbett Life Science, Australia). Allelic variants of CYP1A2 and CYP3A4 were genotyped
by pyrosequencing technology. In particular the CYP 1A2 -163C>A (*1F allele variant) and the
CYP3A4 -392A>G (*1B allele variant) polymorphisms were characterized. Briefly, region
covering the SNPs of interest was amplified by real-time PCR using specific primers set, obtained
by PSQ Assay Design software (Biotage AB and Biosystems, Uppsala, Sweden). The amplicon
was then sequenced by the Pyrosequencer PyroMark ID system (Biotage AB and Biosystems,
Uppsala, Sweden). Genetic analysis showed the patient to be homozygous for the CYP1A2*1F/*1F
and for the CYP3A4*1A/*1A (“wild type”) allelic variants. The CYP1A2*1F polymorphism yields
an isoenzyme that is inducible by nicotine and drugs like omeprazole, but otherwise accounts for
normal metabolism of about 80% of plasma clozapine12A.
Pharmacogenomic analysis showed the patient to be a normal clozapine metabolizer. In fact, her
CYP1A2*1F/*1F genotype does not interfere with clozapine clearance13A, while the
CYP3A4*1A/*1A genotype is the wild-type14A. The use of nicotine would have decreased, rather
than increased her clozapine serum levels, as smoke has a CYP1A2 inducing effect that lowers
clozapine levels15A. Furthermore, omeprazole is also an inducer of CYP1A2, but not in
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Clozapine-associated pancreatitis and the CYP1A2*1F/1F genotype
nonsmokers16A. Moreover, the CYP1A2*1F/*1F genotype is related with lower, rather than higher
blood levels of olanzapine17A, a drug structurally related to clozapine. Hence, there were no
identifiable genetic reasons for which clozapine plasma levels could be so high with both full and
reduced doses of clozapine in the absence of other concomitant factors.
Nitrenium toxicity. Clozapine, like olanzapine, under certain conditions may form a transient
nitrenium+ intermediate metabolite, which may cause toxicity18A. Clozapine may bind activated
neutrophils irreversibly and give rise to an unstable nitrenium19A that in turn induces increased
apoptosis20A and activation of cytokines and immunoglobulins, which further interfere with
CYP1A2 function21A, hence raising toxic clozapine serum levels6. This mechanism, which has been
advanced to explain clozapine agranulocytosis, may fit better to pancreatitis, as it is shared by
olanzapine, which is far less associated with agranulocytosis than clozapine itself. Moreover,
fluperlapine, which does not share this mechanism, yet was stopped from marketing due to the
induction of agranulocytosis22A has not been associated with nitrenium formation.
Comparison to other clinical reports
Therapeutic drug monitoring is not suggested as routine
procedure for clozapine6. Among all reports on clozapine-associated pancreatitis, only SchmitzHübsch’s et al.8 reported blood clozapine values, which were in the therapeutic range, as were
levels at rechallenge in our case. In our case, we recorded higher levels than the therapeutic window
would allow at first assay; we presume that these had to do with the first occurrence of pancreatitis,
and that the second episode occurred at therapeutic serum levels due to sensitization.
Our case compares with other cases reported in literature and differs from many of them in several
aspects (Table A). Differently from Frankenburg and Kando23A, Chengappa et al.24A and Garlipp et
al.25A, we did not observe eosinophilia, but this abnormality is by no means the rule with clozapineassociated pancreatitis. Our patient was asymptomatic, like the cases reported by Bergemann et
al.26A and Garlipp et al.25A; her pancreatic derangement was discovered during routine pancreatic
enzyme examination. The presence of cholelithiasis is intriguing; Chengappa et al.24A also reported
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Clozapine-associated pancreatitis and the CYP1A2*1F/1F genotype
cholelithiasis, and the patient underwent cholecystectomy. Subsequent rechallenge was followed
suit by reappearance of pancreatitis, adding credit to our hypersensitivity hypothesis. Huang’s et
al.27A report of pancreatitis with clozapine several years after cholecystectomy lends support to the
concept that a lithiasic tendency in a patient could foretell subsequent pancreatitis with clozapine.
On the other hand, Schmitz-Hübsch et al.8 reported the case of a patient who developed recurrent
pancreatitis with clozapine and was found with gallstones. After cholecystectomy, there was no
evidence of pancreatitis after clozapine rechallenge and at subsequent follow-up, while psychosis
had improved. At any rate, the relationship between gallstones and susceptibility to clozapineassociated pancreatitis is currently unclear.
One of the criteria to establish the strength of the association with a given side effect is the
disappearance of the effect upon discontinuation and its reappearance after rechallenge. Comprising
our report, seven cases were rechallenged with clozapine and in four of them and in our case
pancreatitis reoccurred23A,24A,26A,27A, while in two it did not8,28A.
Supplemental References
1A. Laghate VD, Gupta SB. Acute pancreatitis and diabetic ketoacidosis in non-diabetic person
while on treatment with sodium valproate, chlorpromazine and haloperidol. J Assoc Physicians
India 2004;52:257-8.
2A. Gasse C, Jacobsen J, Pedersen L et al. Risk of hospitalization for acute pancreatitis associated
with conventional and atypical antipsychotics: a population-based case-control study.
Pharmacotherapy 2008;28:27-34.
3A. Koller EA, Cross JT, Doraiswamy PM, Malozowski SN. Pancreatitis associated with atypical
antipsychotics: from the Food and Drug Administration’s MedWatch surveillance system and
published reports. Pharmacotherapy 2003;23:1123-30.
4
Clozapine-associated pancreatitis and the CYP1A2*1F/1F genotype
4A. Cerulli TR, Alkoc SC, Salzman C. Effects of psychotropic medications on pancreatic function:
a review. Harv Rev Psychiatry 1999;7:54-60.
5A. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a
comprehensive literature review. CNS Drugs 2005;19(Suppl 1):1-93.
6A. Ventura J, Lukoff D, Nuechterlein KH et al. Manual for the Expanded Brief Psychiatric Rating
Scale. Int J Methods Psychiatr Res 1993;3:227-44.
7A. Naranjo CA, Busto U, Sellers EM et al. A method for estimating the probability of adverse
drug reactions. Clin Pharmacol Ther 1981;30:239-45.
8A. De Campos T, Assef JC, Rasslan S. Questions about the use of antibiotics in acute pancreatitis.
World J Emerg Surg 2006;1:20.
9A. Chetty M, Murray M. CYP-mediated clozapine interactions: how predictable are they? Curr
Drug Metab 2007;8:307-13.
10A. Urichuk L, Prior TI, Dursun S, Baker G. Metabolism of atypical antipsychotics: involvement
of cytochrome p450 enzymes and relevance for drug-drug interactions. Curr Drug Metab
2008;9:410-8.
11A. Zhou SF, Wang B, Yang LP, Liu JP. Structure, function, regulation and polymorphism and
the clinical significance of human cytochrome P450 1A2. Drug Metab Rev 2010;42:268-354.
12A. Jaquenoud Sirot E, Knezevic B, Morena GP et al. ABCB1 and cytochrome P450
polymorphisms: clinical pharmacogenetics of clozapine. J Clin Psychopharmacol 2009;29:31926.
13A. Kootstra-Ros JE, Smallegoor W, van der Weide J. The cytochrome P450 CYP1A2 genetic
polymorphisms *1F and *1D do not affect clozapine clearance in a group of schizophrenic
patients. Ann Clin Biochem 2005;42:216-9.
5
Clozapine-associated pancreatitis and the CYP1A2*1F/1F genotype
14A. Garsa AA, McLeod HL, Marsh S. CYP3A4 and CYP3A5 genotyping by Pyrosequencing.
BMC Med Genet 2005;6:19.
15A. van der Weide J, Steijns LS, van Weelden MJ. The effect of smoking and cytochrome P450
CYP1A2 genetic polymorphism on clozapine clearance and dose requirement.
Pharmacogenetics 2003;13:169-72.
16A. Mookhoek EJ, Loonen AJ. Retrospective evaluation of the effect of omeprazole on clozapine
metabolism. Pharm World Sci 2004;26:180-2.
17A. Laika B, Leucht S, Heres S et al. Pharmacogenetics and olanzapine treatment: CYP1A2*1F
and serotonergic polymorphisms influence therapeutic outcome. Pharmacogenomics J
2010;10:20-9.
18A. Sikora A, Adamus J, Marcinek A. Disproportionation of clozapine radical: a link between
one-electron oxidation of clozapine and formation of its nitrenium cation. Chem Res Toxicol
2007;20:1093-8.
19A. Liu ZC, Uetrecht JP. Clozapine is oxidized by activated human neutrophils to a reactive
nitrenium ion that irreversibly binds to the cells. J Pharmacol Exp Ther 1995;275:1476-83.
20A. Williams DP, Pirmohamed M, Naisbitt DJ et al. Induction of metabolism-dependent and independent neutrophil apoptosis by clozapine. Mol Pharmacol 2000;58:207-16.
21A. Haack MJ, Bak ML, Beurskens R et al. Toxic rise of clozapine plasma concentrations in
relation to inflammation. Eur Neuropsychopharmacol 2003;13:381-5.
22A. Meyer JM. Novel antipsychotics and severe hyperlipidemia. J Clin Psychopharmacol
2001;21:369-74.
23A. Frankenburg FR, Kando J. Eosinophilia, clozapine, and pancreatitis. Lancet 1992;340:251.
24A. Chengappa KNR, Pelucio M, Baker RW, Cole D. Recurrent pancreatitis on clozapine rechallenge. J Psychopharmacol 1995;9:381-2.
6
Clozapine-associated pancreatitis and the CYP1A2*1F/1F genotype
25A. Garlipp P, Rosenthal O, Haltenhof H, Machleidt W. The development of a clinical syndrome
of asymptomatic pancreatitis and eosinophilia after treatment with clozapine in schizophrenia:
implications for clinical care, recognition and management. J Psychopharmacol 2002;16:399400.
26A. Bergemann N, Ehrig C, Diebold K et al. Asymptomatic pancreatitis associated with clozapine.
Pharmacopsychiatry 1999;32:78-80.
27A. Huang YJ, Lane HY, Liao CH, Huang CC. Recurrent pancreatitis without eosinophilia on
clozapine rechallenge. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:1561-2.
28A. Fullerton F, McPhillips M, Edelman K, Riccio M. Acute pancreatitis in association with
clozapine. New Trends in Experimental and Clinical Psychiatry 1994;10:149-51.
29A. Martin A. Acute pancreatitis associated with clozapine use. Am J Psychiatry 1992;149:714.
30A. Jubert P, Fernández R, Ruiz A. Clozapine-related pancreatitis. Ann Intern Med 1994;121:7223 (erratum, 1995;122:397).
31A. Gatto EM, Castronuovo AP, Uribe Roca MC. Clozapine and pancreatitis. Clin
Neuropharmacol 1998;21:203.
32A. Cerulli TR. Clozapine-associated pancreatitis. Harv Rev Psychiatry 1999;7:61-3.
33A. Wehmeier PM, Heiser P, Remschmidt H. Pancreatitis followed by pericardial effusion in an
adolescent treated with clozapine. J Clin Psychopharmacol 2003;23:102-3.
34A. Bayard JM, Descamps OS, Evrard S et al. Case report: acute pancreatitis induced by
Clozapine. Acta Gastroenterol Belg 2005;68:9294.
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