- Email: [email protected]
Clozapine toxicity: A discussion of pharmacokinetic factors
Asian Journal of Psychiatry 1 (2008) 47–49
Contents lists available at ScienceDirect
Asian Journal of Psychiatry journal homepage: www.elsevier.com/locate/ajp
Clozapine toxicity: A discussion of pharmacokinetic factors Mujeeb U. Shad * University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd. NE5.110G, Dallas, TX 75390-9127, United States
A R T I C L E I N F O
A B S T R A C T
Article history: Received 13 August 2008 Accepted 25 September 2008
This report seeks to analyze and discuss different pharmacokinetic factors that might be responsible for a case of clozapine toxicity on a conventional clozapine dose. A 41-year-old Caucasian male with schizoaffective disorder was cross-titrated to 400 mg/day of clozapine to manage inadequate response on 6 mg/day of risperidone. A week later the patient became gradually confused and disoriented and eventually lost consciousness. The combined clozapine and norclozapine levels were elevated at 2500 ng/ mL. Patient’s symptoms resolved after clozapine was reduced to 75 mg/day with a reduction in clozapine and norclozapine levels to 420 ng/mL. Toxic clozapine levels may result from abnormal drug absorption, distribution, metabolism or elimination. Changes in absorption and/or distribution are unlikely to explain the toxic levels as clozapine has relatively high oral bioavailability at steady state and a large volume of distribution. In terms of metabolism, clozapine is primarily metabolized by CYP1A2, which biotransforms clozapine to norclozapine. However, it is unlikely that CYP1A2 was responsible, as any reduction in CYP1A2 activity would have likely altered clozapine and norclozapine ratio, which was not observed in this patient. Involvement of other CYP enzymes in the development of clozapine toxicity was ruled out through genotyping. Since liver and renal function tests were also within normal limit, it is difficult to pinpoint a single pharmacokinetic factor responsible for unusually high clozapine and norclozapine levels in this patient. However, a combination of various pharmacokinetic factors may provide an explanation for clozapine toxicity in this patient. Conclusion: Some patients can develop unusually high levels of clozapine and/or its metabolites on routine clozapine dosages resulting in clinically serious adverse effects as observed in our patient. ß 2008 Published by Elsevier B.V.
Keywords: Clozapine Toxicity Pharmacokinetic Factors
1. Introduction Build up of toxic clozapine levels on conventional doses could be due to abnormal drug absorption, distribution, metabolism, and elimination. Using this case as a model, each of these pharmacokinetic factors will be analyzed to identify which of these factor(s) might be responsible for clozapine toxicity in this patient on a conventional dose of clozapine. 2. Case summary A 41-year-old Caucasian male with a diagnosis of schizoaffective disorder, bipolar type was switched by s 2-week cross titration from 6 mg/day of risperidone to 300 mg/day of clozapine due to inadequate response. This patient was also taking lithium 1200 mg/day and propranolol 80 mg/day (for the treatment of akathisia from past antipsychotic therapy). However, when the
* Tel.: +1 214 645 2779; fax: +1 214 645 2786. E-mail address: [email protected]. 1876-2018/$ – see front matter ß 2008 Published by Elsevier B.V. doi:10.1016/j.ajp.2008.09.001
patient did not show any objective or subjective signs of improvement after 4 weeks, the clozapine dose was increased to 400 mg/day. One week later, during his regular visits to the clinic, the patient looked confused with slurred speech and coarse tremors in his upper extremities. The patient admitted consuming 5 cans of beer over the last week. Of note, patient did have a history of alcohol problems in the past. To rule out alcohol-induced changes, clozapine and lithium levels were requested, but not drawn due to patient’s non-adherence. The next day, the patient became more confused, lethargic, unsteady, disoriented and eventually passed out. The patient was taken to an emergency department of a local hospital where he was reported to have ‘‘petit mal’’ like activity. In addition, he was noticed to be disoriented, dizzy, and ‘‘pale and wasted’’. Otherwise the physical examination was within normal limits and no liver enlargement or any other sign of liver disease was observed. There was no report of tremors, jerky movements, tongue twitching or gait abnormalities. In addition, there was no evidence of clozapine or lithium overdose based on information provided by the family and the pill count. Patient was reported to
M.U. Shad / Asian Journal of Psychiatry 1 (2008) 47–49
48
be dehydrated and was diagnosed with postural hypotension and mild leukocytosis (12.3 109 L 1). After the administration of intravenous fluids, the patient reportedly looked better and was sent home. While in the emergency department, clozapine and lithium levels were finally drawn and the clozapine dose was decreased to 150 mg/day. Over the next two days, the patient’s symptoms resolved. The lithium level was almost the same (i.e., 1 mEq/L) as that observed 6 months earlier (i.e., 0.9 mEq/L) at the same lithium dose of 1200 mg/d, but clozapine and norclozapine levels were elevated at 1500 and 1000 ng/mL, respectively. These clozapine and norclozapine levels were much higher than expected (mean steady-state concentration of 372 and 116 ng/mL, respectively expected on a dosing range of 300–450 mg/day) (Perry et al., 1991). Although minimum effective levels for clozapine have been documented, the upper limit of therapeutic clozapine levels is not well established and may significantly vary from patient to patient (CLOZARIL (Clozapine) Novartis, 2001b). However, we observed a combined clozapine and norclozapine level of 2500 ng/mL, which is considered toxic for most, if not all, patients. After a reduction in clozapine dose to 150 mg/day, clozapine and norclozapine levels decreased to 550 and 360 ng/ mL, respectively associated with resolution of symptoms within two days. Later, after clozapine was further reduced to 75 mg/d, clozapine and norclozapine levels decreased to 260 and 160 ng/ mL, respectively. Dosages of propranolol and lithium were also decreased to 40 mg/day and 900 mg/day, respectively. The patient was non-reactive for hepatitis B and C. Patient did have a history of excessive alcohol use in the past and a recently reported alcohol use as reported by his mother. However, both patient and his mother denied any other drug history, including history of intravenous drugs. A score of 6 on the Naranjo ADR Probability Scale suggests that the toxic clozapine level was the probable cause of adverse effects in this patient (Naranjo et al., 1981). In terms of therapeutic drug monitoring (TDM), six plasma levels of clozapine plus norclozapine were drawn over a period of about 2 years. All plasma levels were drawn after 12 h of the last dose under steady state and were analyzed by the same laboratory using gas chromatography. During the 2-year period no adverse effects were reported and all clozapine and norclozapine levels were mostly consistent with the dose, suggesting adherence with clozapine treatment (Table 1). The patient was genotyped for CYP2C9/10, CYP 2C19, CYP 2D6, CYP 2E1 and NAT-2 to determine whether a genetic polymorphism could be responsible for his toxic levels. In addition, the liver and renal function and urine electrolytes were within normal limits and no blood alcohol was detected during the ER visit.
3. Discussion Although, clozapine toxicity on regular daily doses of clozapine has been well-documented in an earlier report (Khan and Preskorn, 2005) this discussion will provide an analysis of pharmacokinetic factors (i.e., absorption, distribution, metabolism, and elimination) that could explain toxic levels of clozapine on a conventional dose. 3.1. Absorption The rate of a drug absorption and hepatic clearance determines its oral bioavailability. Clozapine is completely absorbed from the gastrointestinal tract, but due to an extensive first pass metabolism the bioavailability on a single dose is only 27–50% (CLOZARIL (Clozapine) Novartis, 2001b). Thus, the oral bioavailability may be significantly increased if the hepatic function is compromised. But this is unlikely as the routine liver function tests were within normal limits in this patient. However, a recent excessive use of alcohol may have compromised live function sub-clinically to the extent that it contributed to clozapine toxicity in this patient. 3.2. Distribution It is rare to develop toxic levels of a drug as a result of changes in distribution, such as protein displacement reactions, unless the drug involved has a narrow therapeutic index and a small volume of distribution. Although clozapine may have a relatively narrow therapeutic index, it has a large volume of distribution (4.6 L/kg) (CLOZARIL (Clozapine) Novartis, 2001b) and even if displaced from its protein binding sites, clozapine redistributes quickly to the extra-vascular regions. This redistribution of displaced clozapine will have a buffering effect and therefore a protein displacement interaction would be unlikely, provided that metabolism and elimination of the drug is not compromised. Another factor that can alter the distribution of a drug is the amount of protein available to bind a drug. Therefore an increase in alpha-1 acid glycoprotein (AAG) as a result of cancer, infections, and stress may increase the protein binding of drugs like clozapine thereby increasing its plasma levels. However, this is unlikely to be the case because serious adverse effects, as observed in our patient, indicate an increase in free and active clozapine rather than protein bound clozapine. Additionally this patient was not suffering from any such condition at the time he developed toxic clozapine levels. Besides this patient experienced an increase in total clozapine levels, which cannot be explained by changes in protein binding. However, it remains a possibility that significant dehydration may have contributed to the clozapine toxicity.
Table 1 The relationship between clozapine dose, plasma levels, and clearance. Levels drawna
CLZ dose (mg/d)
CLZ levels (ng/mL)
CLZ CLb dose/level
NCLZ levels (ng/mL)
Total level (ng/mL)
CLZ/NCLZ ratioc
Caffd (mg/d)
Lie (mg/d)
PRPf (mg/d)
0-mon 2-mon 3-mon 13-mon 21-mon 23-mon
400 150 75 75 75 75
1500 550 260 269 179 337
185 189 200 194 291 154
1000 360 160 180 140 228
2500 910 420 449 319 565
1.5 1.5 1.6 1.5 1.3 1.5
204 136 136 68 68 68
1200 900 900 900 900 900
80 40 40 60 60 60
a b c d e f
Time line for levels drawn; mon = months. Estimated clozapine clearance (mL/mt) = daily clozapine dose (mg/d) divided by minutes/day and steady state clozapine level (ng/mL). Clozapine levels (ng/mL) divided by norclozapine levels (ng/mL). Caffeine; Daily intake of caffeine is calculated from the number of soda cans patient used every day, one can = 34 mg of caffeine. Lithium. Propranolol.
M.U. Shad / Asian Journal of Psychiatry 1 (2008) 47–49
49
3.3. Metabolism
3.4. Elimination
Toxic levels of a drug like clozapine that undergoes extensive hepatic metabolism could result from a reduced activity of enzymes involved in clozapine metabolism. A brief discussion of clozapine metabolism will help understand different metabolic factors involved in the development of toxic levels of clozapine and its metabolite, norclozapine. Clozapine utilizes multiple metabolic pathways to be eliminated from the body. Prior to elimination, clozapine is biotransformed to norclozapine, N-oxide clozapine and hydroxy metabolites (Pirmohamed et al., 1995). Cytochrome P-450 (CYP) 1A2 is the main enzyme mediating formation of norclozapine, a major metabolite of clozapine, where as clozapine N-oxide seems to be metabolized by multiple CYP enzymes: CYP 3A4, 2C9/10, and 2E1 (Pirmohamed et al., 1995). In addition, there is evidence to support that flavin-containing monooxegenase-3 (FMO-3) mediates N-oxidation of clozapine (Pirmohamed et al., 1995). Less is known about the hydroxy metabolites of clozapine however, CYP 2D6 may be involved in its metabolism (Pirmohamed et al., 1995). The pharmacological activity of metabolites is unclear, but norclozapine and N-oxide clozapine might be pharmacologically active (CLOZARIL (Clozapine) Novartis, 2001a). Genetic polymorphism of some CYP enzymes can account for poor metabolism of some drugs. However, genotyping did not reveal any genetic deficiency of any of the CYP enzymes tested. Therefore, the build up of toxic plasma levels of clozapine and norclozapine in this patient cannot be explained on the basis of polymorphism of any of the above enzymes. Although CYP1A2 was not genotyped, polymorphism of this enzyme was unlikely to have been responsible for toxic levels of clozapine and norclozapine in this patient. Since such a polymorphism would have altered the normal clozapine and norclozapine (CLZ/NCLZ) ratio, which significantly correlates with CYP1A2 activity (Bertilsson et al., 1994). This view is supported by a significant increase in average CLZ/NCLZ ratio from 1.7 to 4.2 (Dequardo and Roberts, 1996) when used concomitantly with fluvoxamine, a potent inhibitor of CYP1A2 (Hiemke et al., 1994; Weigmann et al., 1993). Likewise a study by Perry et al. (1991) observed a CLZ/NCLZ ratio of 3.2 in 29 physically healthy patients on a daily dose of 300–450 mg. The CLZ/NCLZ ratio of 1.5 observed in our patient actually suggests that his CYP 1A2 activity was higher then the average patient in the study by Perry et al. (1991). The relatively higher CYP1A2 activity in our patient in comparison to patients in aforementioned study cannot be explained on the basis CYP1A2 induction by cigarette smoking, as our patient has been a non-smoker for several years. Unlike smoking, concomitant use of caffeine and propranolol, both substrates for CYP1A2, can increase clozapine levels as a result of competitive inhibition of CYP1A2 (Carrillo et al., 1998; Johnson et al., 2000). However this is unlikely because neither the clearance nor the CLZ/NCLZ ratio changed with a change in caffeine and propranolol intake. Lithium is unlikely to alter clozapine metabolism as lithium is a salt and is not known to affect CYP enzymes function. In addition, a decrease in lithium dose from 1200 to 900 mg/d did not result in any significant change in CLZ/NCLZ ratio or clozapine clearance (Table 1). However, we cannot completely rule out the possibility of a drug–drug interaction with propranolol and/or caffeine contributing to clozapine toxicity in this patient.
Drug toxicity could result from slow elimination due to compromised hepatic and renal function. Propranolol can reduce hepatic and renal arterial blood flow and compromise hepatic and renal function. However, this is unlikely in our patient as a significant reduction in propranolol dose from 80 to 40 mg/d did not result in any significant change in clozapine and/or norclozapine levels (Table 1). In addition, renal function and urine electrolytes were within normal limits, which almost rules out the likelihood of a renal pathology and the syndrome of inappropriate secretion of anti-diuretic hormone (SIADH). The normal renal function also rules out lithium-induced renal toxicity. However, it remains a possibility that a combination of various factors, such propranolol effect on compromising clozapine elimination to some extent along with alcohol-induced effects on cardiac and renal function may have contributed to this complex case of clozapine toxicity along with several other factors as discussed above. 4. Conclusion The findings from this case report suggest that multiple pharmacokinetic mechanisms, such as a recent excessive use of alcohol, dehydration, and potential drug–drug interactions with caffeine and propranolol, may have contributed to unusually high clozapine and norclozapine levels in this patient. However, regardless of the etiology, the most important message is to understand that patients can develop toxic levels at routine clozapine doses resulting in clinically serious adverse effects. Thus, use of therapeutic drug monitoring in patients experiencing unexpected adverse effects at expected clozapine dosages, as occurred in our patient, may permit early detection of abnormal clozapine levels thus preventing clinically serious adverse effects. References Bertilsson, L., Carrillo, J., Dahl, M.L., Llerna, A., Alm, C., Bondesson, U., et al., 1994. Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test. Am. J. Psychiatry 38, 471–473. Carrillo, J.A., Herraiz, A.G., Ramos, S.I., Benitez, J., 1998. Effects of caffeine withdrawal from the diet on the metabolism of clozapine in schizophrenic patients. J. Clin. Psychopharmacol. 18, 311–316. CLOZARIL (Clozapine) Novartis, 2001a. Physicians’ Desk Reference. 55, pp. 2042– 2044. CLOZARIL (Clozapine) Novartis, 2001b. AHFS Drug Information, 27, pp. 1739–1742. Dequardo, J., Roberts, M., 1996. Elevated clozapine levels after fluvoxamine initiation (Letter). Am. J. Psychiatry 153, 840–841. Hiemke, C., Weigmann, H., Hartter, S., Dahmen, N., Wetzel, H., Muller, H., 1994. Elevated levels of clozapine in serum after addition of fluvoxamine. J. Clin. Psychopharmacol. 14, 279–281. Johnson, J.A., Herring, V.L., Wolfe, M.S., Relling, M.V., 2000. CYP1A2 and CYP2D6 4hydroxylates propranolol and both reactions exhibit racial differences. J. Pharmacol. Exp. Ther. 294, 1099–1105. Khan, A.Y., Preskorn, S.H., 2005. Examining concentration-dependent toxicity of clozapine: role of therapeutic drug monitoring. J. Psychiatr. Pract. 11 (5), 289–301. Naranjo, C.A., Busto, U., Sellers, P., Sandor, P., Ruiz, I., Roberts, E.A., et al., 1981. A method for estimating the probability of adverse drug reactions. Clin. Pharmacol. Ther. 30, 239–245. Perry, P.J., Miller, D.D., Arndt, S.V., Cadoret, R.J., 1991. Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am. J. Psychiatry 148, 231–235. Pirmohamed, M., Williams, D., Madden, S., Templeton, E., Park, K.B., 1995. Metabolism and bioactivation of Clozapine by human liver in vitro. J. Pharmacol. Exp. Ther. 272, 984–990. Weigmann, H., Muller, H., Dahmen, N., 1993. Interactions of fluvoxamine with the metabolism of clozapine (Letter). Am. J. Psychiatry 26, 209.
Contents lists available at ScienceDirect
Asian Journal of Psychiatry journal homepage: www.elsevier.com/locate/ajp
Clozapine toxicity: A discussion of pharmacokinetic factors Mujeeb U. Shad * University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd. NE5.110G, Dallas, TX 75390-9127, United States
A R T I C L E I N F O
A B S T R A C T
Article history: Received 13 August 2008 Accepted 25 September 2008
This report seeks to analyze and discuss different pharmacokinetic factors that might be responsible for a case of clozapine toxicity on a conventional clozapine dose. A 41-year-old Caucasian male with schizoaffective disorder was cross-titrated to 400 mg/day of clozapine to manage inadequate response on 6 mg/day of risperidone. A week later the patient became gradually confused and disoriented and eventually lost consciousness. The combined clozapine and norclozapine levels were elevated at 2500 ng/ mL. Patient’s symptoms resolved after clozapine was reduced to 75 mg/day with a reduction in clozapine and norclozapine levels to 420 ng/mL. Toxic clozapine levels may result from abnormal drug absorption, distribution, metabolism or elimination. Changes in absorption and/or distribution are unlikely to explain the toxic levels as clozapine has relatively high oral bioavailability at steady state and a large volume of distribution. In terms of metabolism, clozapine is primarily metabolized by CYP1A2, which biotransforms clozapine to norclozapine. However, it is unlikely that CYP1A2 was responsible, as any reduction in CYP1A2 activity would have likely altered clozapine and norclozapine ratio, which was not observed in this patient. Involvement of other CYP enzymes in the development of clozapine toxicity was ruled out through genotyping. Since liver and renal function tests were also within normal limit, it is difficult to pinpoint a single pharmacokinetic factor responsible for unusually high clozapine and norclozapine levels in this patient. However, a combination of various pharmacokinetic factors may provide an explanation for clozapine toxicity in this patient. Conclusion: Some patients can develop unusually high levels of clozapine and/or its metabolites on routine clozapine dosages resulting in clinically serious adverse effects as observed in our patient. ß 2008 Published by Elsevier B.V.
Keywords: Clozapine Toxicity Pharmacokinetic Factors
1. Introduction Build up of toxic clozapine levels on conventional doses could be due to abnormal drug absorption, distribution, metabolism, and elimination. Using this case as a model, each of these pharmacokinetic factors will be analyzed to identify which of these factor(s) might be responsible for clozapine toxicity in this patient on a conventional dose of clozapine. 2. Case summary A 41-year-old Caucasian male with a diagnosis of schizoaffective disorder, bipolar type was switched by s 2-week cross titration from 6 mg/day of risperidone to 300 mg/day of clozapine due to inadequate response. This patient was also taking lithium 1200 mg/day and propranolol 80 mg/day (for the treatment of akathisia from past antipsychotic therapy). However, when the
* Tel.: +1 214 645 2779; fax: +1 214 645 2786. E-mail address: [email protected]. 1876-2018/$ – see front matter ß 2008 Published by Elsevier B.V. doi:10.1016/j.ajp.2008.09.001
patient did not show any objective or subjective signs of improvement after 4 weeks, the clozapine dose was increased to 400 mg/day. One week later, during his regular visits to the clinic, the patient looked confused with slurred speech and coarse tremors in his upper extremities. The patient admitted consuming 5 cans of beer over the last week. Of note, patient did have a history of alcohol problems in the past. To rule out alcohol-induced changes, clozapine and lithium levels were requested, but not drawn due to patient’s non-adherence. The next day, the patient became more confused, lethargic, unsteady, disoriented and eventually passed out. The patient was taken to an emergency department of a local hospital where he was reported to have ‘‘petit mal’’ like activity. In addition, he was noticed to be disoriented, dizzy, and ‘‘pale and wasted’’. Otherwise the physical examination was within normal limits and no liver enlargement or any other sign of liver disease was observed. There was no report of tremors, jerky movements, tongue twitching or gait abnormalities. In addition, there was no evidence of clozapine or lithium overdose based on information provided by the family and the pill count. Patient was reported to
M.U. Shad / Asian Journal of Psychiatry 1 (2008) 47–49
48
be dehydrated and was diagnosed with postural hypotension and mild leukocytosis (12.3 109 L 1). After the administration of intravenous fluids, the patient reportedly looked better and was sent home. While in the emergency department, clozapine and lithium levels were finally drawn and the clozapine dose was decreased to 150 mg/day. Over the next two days, the patient’s symptoms resolved. The lithium level was almost the same (i.e., 1 mEq/L) as that observed 6 months earlier (i.e., 0.9 mEq/L) at the same lithium dose of 1200 mg/d, but clozapine and norclozapine levels were elevated at 1500 and 1000 ng/mL, respectively. These clozapine and norclozapine levels were much higher than expected (mean steady-state concentration of 372 and 116 ng/mL, respectively expected on a dosing range of 300–450 mg/day) (Perry et al., 1991). Although minimum effective levels for clozapine have been documented, the upper limit of therapeutic clozapine levels is not well established and may significantly vary from patient to patient (CLOZARIL (Clozapine) Novartis, 2001b). However, we observed a combined clozapine and norclozapine level of 2500 ng/mL, which is considered toxic for most, if not all, patients. After a reduction in clozapine dose to 150 mg/day, clozapine and norclozapine levels decreased to 550 and 360 ng/ mL, respectively associated with resolution of symptoms within two days. Later, after clozapine was further reduced to 75 mg/d, clozapine and norclozapine levels decreased to 260 and 160 ng/ mL, respectively. Dosages of propranolol and lithium were also decreased to 40 mg/day and 900 mg/day, respectively. The patient was non-reactive for hepatitis B and C. Patient did have a history of excessive alcohol use in the past and a recently reported alcohol use as reported by his mother. However, both patient and his mother denied any other drug history, including history of intravenous drugs. A score of 6 on the Naranjo ADR Probability Scale suggests that the toxic clozapine level was the probable cause of adverse effects in this patient (Naranjo et al., 1981). In terms of therapeutic drug monitoring (TDM), six plasma levels of clozapine plus norclozapine were drawn over a period of about 2 years. All plasma levels were drawn after 12 h of the last dose under steady state and were analyzed by the same laboratory using gas chromatography. During the 2-year period no adverse effects were reported and all clozapine and norclozapine levels were mostly consistent with the dose, suggesting adherence with clozapine treatment (Table 1). The patient was genotyped for CYP2C9/10, CYP 2C19, CYP 2D6, CYP 2E1 and NAT-2 to determine whether a genetic polymorphism could be responsible for his toxic levels. In addition, the liver and renal function and urine electrolytes were within normal limits and no blood alcohol was detected during the ER visit.
3. Discussion Although, clozapine toxicity on regular daily doses of clozapine has been well-documented in an earlier report (Khan and Preskorn, 2005) this discussion will provide an analysis of pharmacokinetic factors (i.e., absorption, distribution, metabolism, and elimination) that could explain toxic levels of clozapine on a conventional dose. 3.1. Absorption The rate of a drug absorption and hepatic clearance determines its oral bioavailability. Clozapine is completely absorbed from the gastrointestinal tract, but due to an extensive first pass metabolism the bioavailability on a single dose is only 27–50% (CLOZARIL (Clozapine) Novartis, 2001b). Thus, the oral bioavailability may be significantly increased if the hepatic function is compromised. But this is unlikely as the routine liver function tests were within normal limits in this patient. However, a recent excessive use of alcohol may have compromised live function sub-clinically to the extent that it contributed to clozapine toxicity in this patient. 3.2. Distribution It is rare to develop toxic levels of a drug as a result of changes in distribution, such as protein displacement reactions, unless the drug involved has a narrow therapeutic index and a small volume of distribution. Although clozapine may have a relatively narrow therapeutic index, it has a large volume of distribution (4.6 L/kg) (CLOZARIL (Clozapine) Novartis, 2001b) and even if displaced from its protein binding sites, clozapine redistributes quickly to the extra-vascular regions. This redistribution of displaced clozapine will have a buffering effect and therefore a protein displacement interaction would be unlikely, provided that metabolism and elimination of the drug is not compromised. Another factor that can alter the distribution of a drug is the amount of protein available to bind a drug. Therefore an increase in alpha-1 acid glycoprotein (AAG) as a result of cancer, infections, and stress may increase the protein binding of drugs like clozapine thereby increasing its plasma levels. However, this is unlikely to be the case because serious adverse effects, as observed in our patient, indicate an increase in free and active clozapine rather than protein bound clozapine. Additionally this patient was not suffering from any such condition at the time he developed toxic clozapine levels. Besides this patient experienced an increase in total clozapine levels, which cannot be explained by changes in protein binding. However, it remains a possibility that significant dehydration may have contributed to the clozapine toxicity.
Table 1 The relationship between clozapine dose, plasma levels, and clearance. Levels drawna
CLZ dose (mg/d)
CLZ levels (ng/mL)
CLZ CLb dose/level
NCLZ levels (ng/mL)
Total level (ng/mL)
CLZ/NCLZ ratioc
Caffd (mg/d)
Lie (mg/d)
PRPf (mg/d)
0-mon 2-mon 3-mon 13-mon 21-mon 23-mon
400 150 75 75 75 75
1500 550 260 269 179 337
185 189 200 194 291 154
1000 360 160 180 140 228
2500 910 420 449 319 565
1.5 1.5 1.6 1.5 1.3 1.5
204 136 136 68 68 68
1200 900 900 900 900 900
80 40 40 60 60 60
a b c d e f
Time line for levels drawn; mon = months. Estimated clozapine clearance (mL/mt) = daily clozapine dose (mg/d) divided by minutes/day and steady state clozapine level (ng/mL). Clozapine levels (ng/mL) divided by norclozapine levels (ng/mL). Caffeine; Daily intake of caffeine is calculated from the number of soda cans patient used every day, one can = 34 mg of caffeine. Lithium. Propranolol.
M.U. Shad / Asian Journal of Psychiatry 1 (2008) 47–49
49
3.3. Metabolism
3.4. Elimination
Toxic levels of a drug like clozapine that undergoes extensive hepatic metabolism could result from a reduced activity of enzymes involved in clozapine metabolism. A brief discussion of clozapine metabolism will help understand different metabolic factors involved in the development of toxic levels of clozapine and its metabolite, norclozapine. Clozapine utilizes multiple metabolic pathways to be eliminated from the body. Prior to elimination, clozapine is biotransformed to norclozapine, N-oxide clozapine and hydroxy metabolites (Pirmohamed et al., 1995). Cytochrome P-450 (CYP) 1A2 is the main enzyme mediating formation of norclozapine, a major metabolite of clozapine, where as clozapine N-oxide seems to be metabolized by multiple CYP enzymes: CYP 3A4, 2C9/10, and 2E1 (Pirmohamed et al., 1995). In addition, there is evidence to support that flavin-containing monooxegenase-3 (FMO-3) mediates N-oxidation of clozapine (Pirmohamed et al., 1995). Less is known about the hydroxy metabolites of clozapine however, CYP 2D6 may be involved in its metabolism (Pirmohamed et al., 1995). The pharmacological activity of metabolites is unclear, but norclozapine and N-oxide clozapine might be pharmacologically active (CLOZARIL (Clozapine) Novartis, 2001a). Genetic polymorphism of some CYP enzymes can account for poor metabolism of some drugs. However, genotyping did not reveal any genetic deficiency of any of the CYP enzymes tested. Therefore, the build up of toxic plasma levels of clozapine and norclozapine in this patient cannot be explained on the basis of polymorphism of any of the above enzymes. Although CYP1A2 was not genotyped, polymorphism of this enzyme was unlikely to have been responsible for toxic levels of clozapine and norclozapine in this patient. Since such a polymorphism would have altered the normal clozapine and norclozapine (CLZ/NCLZ) ratio, which significantly correlates with CYP1A2 activity (Bertilsson et al., 1994). This view is supported by a significant increase in average CLZ/NCLZ ratio from 1.7 to 4.2 (Dequardo and Roberts, 1996) when used concomitantly with fluvoxamine, a potent inhibitor of CYP1A2 (Hiemke et al., 1994; Weigmann et al., 1993). Likewise a study by Perry et al. (1991) observed a CLZ/NCLZ ratio of 3.2 in 29 physically healthy patients on a daily dose of 300–450 mg. The CLZ/NCLZ ratio of 1.5 observed in our patient actually suggests that his CYP 1A2 activity was higher then the average patient in the study by Perry et al. (1991). The relatively higher CYP1A2 activity in our patient in comparison to patients in aforementioned study cannot be explained on the basis CYP1A2 induction by cigarette smoking, as our patient has been a non-smoker for several years. Unlike smoking, concomitant use of caffeine and propranolol, both substrates for CYP1A2, can increase clozapine levels as a result of competitive inhibition of CYP1A2 (Carrillo et al., 1998; Johnson et al., 2000). However this is unlikely because neither the clearance nor the CLZ/NCLZ ratio changed with a change in caffeine and propranolol intake. Lithium is unlikely to alter clozapine metabolism as lithium is a salt and is not known to affect CYP enzymes function. In addition, a decrease in lithium dose from 1200 to 900 mg/d did not result in any significant change in CLZ/NCLZ ratio or clozapine clearance (Table 1). However, we cannot completely rule out the possibility of a drug–drug interaction with propranolol and/or caffeine contributing to clozapine toxicity in this patient.
Drug toxicity could result from slow elimination due to compromised hepatic and renal function. Propranolol can reduce hepatic and renal arterial blood flow and compromise hepatic and renal function. However, this is unlikely in our patient as a significant reduction in propranolol dose from 80 to 40 mg/d did not result in any significant change in clozapine and/or norclozapine levels (Table 1). In addition, renal function and urine electrolytes were within normal limits, which almost rules out the likelihood of a renal pathology and the syndrome of inappropriate secretion of anti-diuretic hormone (SIADH). The normal renal function also rules out lithium-induced renal toxicity. However, it remains a possibility that a combination of various factors, such propranolol effect on compromising clozapine elimination to some extent along with alcohol-induced effects on cardiac and renal function may have contributed to this complex case of clozapine toxicity along with several other factors as discussed above. 4. Conclusion The findings from this case report suggest that multiple pharmacokinetic mechanisms, such as a recent excessive use of alcohol, dehydration, and potential drug–drug interactions with caffeine and propranolol, may have contributed to unusually high clozapine and norclozapine levels in this patient. However, regardless of the etiology, the most important message is to understand that patients can develop toxic levels at routine clozapine doses resulting in clinically serious adverse effects. Thus, use of therapeutic drug monitoring in patients experiencing unexpected adverse effects at expected clozapine dosages, as occurred in our patient, may permit early detection of abnormal clozapine levels thus preventing clinically serious adverse effects. References Bertilsson, L., Carrillo, J., Dahl, M.L., Llerna, A., Alm, C., Bondesson, U., et al., 1994. Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test. Am. J. Psychiatry 38, 471–473. Carrillo, J.A., Herraiz, A.G., Ramos, S.I., Benitez, J., 1998. Effects of caffeine withdrawal from the diet on the metabolism of clozapine in schizophrenic patients. J. Clin. Psychopharmacol. 18, 311–316. CLOZARIL (Clozapine) Novartis, 2001a. Physicians’ Desk Reference. 55, pp. 2042– 2044. CLOZARIL (Clozapine) Novartis, 2001b. AHFS Drug Information, 27, pp. 1739–1742. Dequardo, J., Roberts, M., 1996. Elevated clozapine levels after fluvoxamine initiation (Letter). Am. J. Psychiatry 153, 840–841. Hiemke, C., Weigmann, H., Hartter, S., Dahmen, N., Wetzel, H., Muller, H., 1994. Elevated levels of clozapine in serum after addition of fluvoxamine. J. Clin. Psychopharmacol. 14, 279–281. Johnson, J.A., Herring, V.L., Wolfe, M.S., Relling, M.V., 2000. CYP1A2 and CYP2D6 4hydroxylates propranolol and both reactions exhibit racial differences. J. Pharmacol. Exp. Ther. 294, 1099–1105. Khan, A.Y., Preskorn, S.H., 2005. Examining concentration-dependent toxicity of clozapine: role of therapeutic drug monitoring. J. Psychiatr. Pract. 11 (5), 289–301. Naranjo, C.A., Busto, U., Sellers, P., Sandor, P., Ruiz, I., Roberts, E.A., et al., 1981. A method for estimating the probability of adverse drug reactions. Clin. Pharmacol. Ther. 30, 239–245. Perry, P.J., Miller, D.D., Arndt, S.V., Cadoret, R.J., 1991. Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am. J. Psychiatry 148, 231–235. Pirmohamed, M., Williams, D., Madden, S., Templeton, E., Park, K.B., 1995. Metabolism and bioactivation of Clozapine by human liver in vitro. J. Pharmacol. Exp. Ther. 272, 984–990. Weigmann, H., Muller, H., Dahmen, N., 1993. Interactions of fluvoxamine with the metabolism of clozapine (Letter). Am. J. Psychiatry 26, 209.