Características de la carne

A 35-year-old man with a history of recurrent melancholic major depressive disorder had been stably maintained for over 3 years on a regimen of de- sipramine (Norpramin), 200 mg/day, with a stable blood level of around 150 ng/mL. The patient was also a two-pack-per-day smoker. His father had died in his mid-40s from a myocardial infarction. Accordingly, this patient’s family physician strongly advised the patient to participate in an aggressive smoking cessation program. As part of this program, the physician started the patient on bupropion (Zyban, in this application), titrating to a dosage of 150 mg bid. One week after reaching this dosage, the patient began to ex- perience frequent palpitations and accompanying light-headedness. He re- ported these symptoms to his family physician, who evaluated the patient. The patient’s electrocardiogram showed a sinus tachycardia of 132 beats per minute and QRS interval widening to a duration of 160 msec. The patient was admitted to a telemetry unit, where a desipramine level was drawn be- fore the drug was discontinued, and the result was 623 ng/mL. A week after the desipramine was stopped, his symptoms fully remitted.

Discussion

This is an example of an inhibitor added to a substrate.

Desipramine, as a secondary-amine tricyclic antidepressant, is metabo- lized primarily at 2D6 (Dahl et al. 1993). Bupropion is a relatively potent 2D6 inhibitor, capable of elevating desipramine blood levels to two to five times baseline (GlaxoSmithKline 2001; Kotlyar et al. 2005). Thus, the ad- dition of bupropion (albeit in the form of Zyban) impaired the ability of 2D6 to efficiently metabolize the desipramine, which led to a more than fourfold increase in the desipramine blood level in this case, even though the desipramine dosage had not been changed. The resultant cardiac tox- icity (via excessive quinidine-like effects of toxic tricyclic levels) led to the symptoms of palpitations and dizziness.

References

Dahl ML, Iselius L, Alm C, et al: Polymorphic 2-hydroxylation of desipramine: a population and family study. Eur J Clin Pharmacol 44:445–450, 1993 GlaxoSmithKline: Wellbutrin (package insert). Research Triangle Park, NC, Glaxo-

SmithKline, 2001

Kotlyar M, Brauer LH, Tracy TS, et al: Inhibition of CYP2D6 activity by bupro- pion. J Clin Psychopharmacol 25:226–229, 2005

BLOATED

A 37-year-old woman with a long-standing history of panic disorder had been experiencing only one panic attack per month for the past several years while taking amitriptyline (Elavil), 175 mg/day. At this dosage, her blood level of amitriptyline + nortriptyline ranged from 150 to 180 ng/mL. However, her pet Labrador, who had helped provide a sense of companion- ship and security, finally succumbed to old age and passed away. Following the loss of this cherished pet, her panic attacks increased in frequency (to five times per week) and intensity. In an effort to address this, her psychia- trist added clonazepam (Klonopin), 0.5 mg tid, to her regimen. At the same time the psychiatrist also added paroxetine (Paxil), 10 mg/day for 4 days and 20 mg/day thereafter while simultaneously decreasing the amitriptyline to 150 mg/day. Ten days after starting the paroxetine, the patient began to ex- perience abdominal cramping, back pain, and a pervasive feeling of being bloated. She had a significant decrease in her frequency of bowel move- ments. Her bloating led to increasing nausea and even vomiting. Her in- creasing inability to tolerate oral intake led her to visit the local emergency room. She was admitted to the hospital, where a gastrointestinal workup revealed a partial small bowel obstruction due to an adynamic ileus. Her

amitriptyline + nortriptyline blood level was found to be 694 ng/mL, whereupon she was also placed on a heart monitor (S. Ruths, personal com- munication, June 2002).

Discussion

This is an example of an inhibitor added to a substrate.

Amitriptyline is a tertiary-amine tricyclic antidepressant whose metabo- lism depends most on the intact functioning of 2C19, 3A4, and 2D6, with 1A2 serving as a secondary enzyme. Nortriptyline is amitriptyline’s primary metabolite via demethylation by 2C19 and 3A4. 2D6 catalyzes hydroxylation of both amitriptyline and nortriptyline (Venkatakrishnan et al. 1998, 1999). Paroxetine is a strong competitive inhibitor of 2D6 (von Moltke et al. 1995). Thus, the addition of paroxetine significantly impaired the ability of 2D6 to contribute to the metabolism of amitriptyline and nortriptyline, which led to a three- to fourfold increase in the amitriptyline + nortriptyline blood level despite a modest decrease in amitriptyline dosage (from 175 mg/day to 150 mg/day). The resultant state of tricyclic toxicity led to the patient’s ady- namic ileus and associated cramping, bloating, vomiting, and back pain. It also led to the quinidine-like changes in cardiac conduction that were ob- served after she was placed on a heart monitor.

References

Venkatakrishnan K, Greenblatt DJ, von Moltke LL, et al: Five distinct human cy- tochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4. J Clin Pharmacol 38:112–121, 1998

Venkatakrishnan K, von Moltke LL, Greenblatt DJ: Nortriptyline E-10-hydroxy- lation in vitro is mediated by human CYP2D6 (high affinity) and CYP3A4 (low affinity): implications for interactions with enzyme-inducing drugs. J Clin Pharmacol 39:567–577, 1999

von Moltke LL, Greenblatt DJ, Court MH, et al: Inhibition of alprazolam and de- sipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. J Clin Psy- chopharmacol 15:125–131, 1995

WINDOW

A 42-year-old man with recurrent major depression and a remote history of intravenous drug abuse was being stably maintained on nortriptyline (Pam- elor), 100 mg/day (most recent blood level, 91 ng/mL). A new girlfriend insisted on his obtaining an HIV test before they began to have sexual re- lations, whereupon he discovered that he was HIV positive. After verifying

that this result was not a false positive, his internist prescribed ritonavir (Norvir). Over the next 2 weeks, the patient experienced increasing irrita- bility, dysphoria, insomnia, and demoralization. Fearing that a drug inter- action had occurred, the internist ordered a nortriptyline blood level, which he found had risen to 218 ng/mL. The internist decreased the nortriptyline dosage to 50 mg/day, and another blood level 1 week later was 112 ng/mL. After another week, the depressive symptoms had remitted (K.L. Cozza, personal communication, May 2002).

Discussion

This is an example of an inhibitor added to a substrate.

Nortriptyline is a 2D6 substrate (Sawada and Ohtani 2001), and rito- navir is a 2D6 inhibitor (as well as an inhibitor of most P450 enzymes except 1A2, and a later inducer of 1A2, 2C9, 2C19, and 3A4) (Greenblatt et al. 2000; Llibre et al. 2002; von Moltke et al. 1998). The addition of the ritonavir impaired the ability of 2D6 to efficiently metabolize the nortrip- tyline, thus yielding a higher blood level of nortriptyline even though the dosage had not been increased. Studies have suggested that nortriptyline demonstrates a therapeutic blood level window of 50–150 ng/mL, such that levels below 50 ng/mL and levels above 150 ng/mL tend to be less effective in treating depressive symptoms (Kaplan and Sadock 1998). Hence, the in- crease in the patient’s nortriptyline level from 91 ng/mL to 218 ng/mL caused by ritonavir’s 2D6 inhibition represented a departure from this ther- apeutic window, leading to the emergence of depressive symptoms. (Inci- dentally, decreased antidepressant efficacy when nortriptyline blood levels are greater than 150 ng/mL is thought to be unrelated to the presence of any tricyclic antidepressant toxicity state.) A reduction in the nortriptyline dosage to 50 mg/day compensated for ritonavir’s 2D6 inhibition, leading to a final nortriptyline blood level that was within the therapeutic window and resolution of the patient’s depressive symptoms.

References

Greenblatt DJ, von Moltke LL, Harmatz JS, et al: Alprazolam-ritonavir interaction: implications for product labeling. Clin Pharmacol Ther 67:335–341, 2000 Kaplan H, Sadock B: Kaplan and Sadock’s Synopsis of Psychiatry, Behavioral Sci-

ences/Clinical Psychiatry, 8th Edition. Baltimore, MD, Williams and Wilkins, 1998

Llibre J, Romeu J, Lopez E, et al: Severe interaction between ritonavir and aceno- coumarol. Ann Pharmacother 36:621–623, 2002

Sawada Y, Ohtani H: Pharmacokinetics and drug interactions of antidepressive agents (in Japanese). Nippon Rinsho 59:1539–1545, 2001

von Moltke LL, Greenblatt DJ, Grassi JM, et al: Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir. J Clin Pharma- col 38:106–111, 1998