Drugs That Escape Hepatic Metabolism

Notice of correction 1/8/2013: In Table 1, point 2 now correctly cites reference 22.

In a recent case report,1 Paulzen and colleagues discussed the challenges they faced in treating a woman with psychotic depression who was found to be a cytochrome P450 (CYP) 2D6 ultrarapid metabolizer. She underwent many medication trials and eventually improved only after receiving sulpiride (300 mg/d), the action of which is terminated by renal excretion.

Patients who are abnormal metabolizers, who have liver disease, or who are taking drugs that induce or inhibit CYP enzymes necessitate an awareness of the few drugs in neuropsychopharmacology that are not metabolized by the CYP enzymes in the liver. Knowledge of possible treatment strategies, which may include dose adjustment or selection of drugs not metabolized by CYP enzymes in the liver, can be important in 5 situations in which hepatic metabolism of drugs differs from that expected (Table 1).

Adjusting the Dose

A knowledge of pharmacokinetics and drug interactions may guide dose adjustments in some situations; for example, low rather than standard doses of clomipramine are advisable if augmentation is desired in a patient who is already receiving fluoxetine (a CYP enzyme inhibitor).6

Selecting a Drug Not Metabolized by CYP Enzymes

As an alternative to dose adjustment, clinicians can prescribe drugs that are not metabolized or are only minimally metabolized by the CYP enzymes. A list of such drugs is presented in Table 2.

How Much Is the Drug Metabolized by the Liver?

It helps to know how much a drug is metabolized, if it is metabolized by the liver. For example, only about 20% of topiramate is metabolized in the liver; the remaining 80% is excreted unchanged. However, when enzyme-inducing drugs such as phenytoin or carbamazepine are administered, up to 50% of topiramate may be metabolized.20 Thus, topiramate may be a useful drug in certain, but not all, of the situations in Table 1.

Metabolism via Glucuronidation

Lorazepam and lamotrigine are possible candidates in many of the situations listed in Table 1. Lorazepam is metabolized by glucuronidation, but, because this pathway is relatively spared in liver disease,9 lorazepam is safer than diazepam or chlordiazepoxide in alcoholic patients with hepatic impairment.21 Lamotrigine is also metabolized predominantly by glucuronidation. Like lorazepam, it is vulnerable to factors that induce or impair glucuronidation.18

Selecting a Drug With an Active Metabolite Not Further Metabolized by the Liver

Finally, drugs that have active metabolites that are not further metabolized by the liver can be appropriate in patients who are rapid metabolizers and in those who are receiving CYP enzyme inducers. For example, risperidone (which is metabolized to 9-hydroxyrisperidone, or paliperidone)13 can be considered rather than olanzapine in a schizophrenia patient who is a heavy smoker.7 (For more on how smoking affects metabolism of antipsychotics, see my June column on the topic.) Another example (which could have benefited the patient described by Paulzen et al1) is venlafaxine; this antidepressant is metabolized to desvenlafaxine.11 The actions of paliperidone and desvenlafaxine are terminated principally by renal excretion.11,13

Conclusion

The hepatic metabolism of most neuropsychopharmacologic agents may be altered in various situations, such as when patients also receive drugs that influence the CYP enzymes responsible for drug metabolism or when they smoke or have liver disease. Consequences of altered drug metabolism include compromised medication efficacy or increased medication adverse effects. Corrective measures include appropriate dose adjustments or the use of medications that are not metabolized or are minimally metabolized by the CYP enzymes in the liver.

J Clin Psychiatry 2012;73(7):e889-e890 (doi:10.4088/JCP.12f07726)

© Copyright 2012 Physicians Postgraduate Press, Inc.

Each month in his online column, Dr Andrade considers theoretical and practical ideas in clinical psychopharmacology with a view to update the knowledge and skills of medical practitioners who treat patients with psychiatric conditions.

Department of Clinical Psychopharmacology and Neurotoxicology, National Institute of Mental Health and Neurosciences, Bangalore, India (candrade@psychiatrist.com).
Financial disclosure and more about Dr Andrade.

REFERENCES

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18. Johannessen Landmark C, Patsalos PN. Drug interactions involving the new second- and third-generation antiepileptic drugs. Expert Rev Neurother. 2010;10(1):119-140. PubMed doi:10.1586/ern.09.136

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Volume: 73

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