Desmethylclozapine (DMCZ)

Figure 13.8 • Metabolic pathway of clozapine.

following a single 75-mg dose is 8 hours. Because of several adverse effects, clozapine is only used in refractory cases of schizophrenia. Individuals with a history of seizures or predisposed to seizures should be cautioned when taking clozapine. Similar to other atypical antipsychotic agents, clozapine causes an increased risk of mortality in elderly individuals with dementia-related psychoses.23

Olanzapine. Olanzapine, 2-methyl-4-(4-methyl-1-piper-azinyl)-10h-thieno[2,3-b][1,5] benzodiazepine (Zyprexa), is a yellow crystalline solid that is essentially insoluble in water. Olanzapine orally disintegrating tablets (Zyprexa Zydis) is a solid dosage form that immediately disintegrates when exposed to saliva. This product is useful for elderly patients who have difficulty in swallowing. An injectable form, olanzapine for injection (Zyprexa IM), is indicated for agitation associated with schizophrenia or bipolar I mania. Olanzapine is combined with fluoxetine (Symbyax) for use in depression that is associated with bipolar I disorder. Peak concentrations of oral olanzapine are reached at 6 hours after oral administration, and absorption of the compound is not affected by food.23 Olanzapine is 93% bound to plasma proteins, and its mean half-life is 27 hours.112,113 Olanzapine undergoes extensive first-pass metabolism, and about 40% of an oral dose is metabolized prior to reaching the systemic circulation. The major metabolite of olanzapine in human subjects is the 10-n-glucuronide. Other human metabolites that have identified include the n-desmethyl, the n-oxide, and the 2-hydrox-ymethyl metabolites (Fig. 13.9). The n-desmethyl and the 2-hydroxymethyl metabolites are products of CYP1A2 and CYP2D6 action, respectively.112,113

Olanzapine binds with high affinity at DA D2, 5-HT2A, 5-HT2C, 5-HT6, a1, and H1 histamine receptors. The effects of olanzapine for the treatment of schizophrenia are presumably mediated through antagonism at D2 and 5-HT2A receptors.23,112,113 The use of olanzapine in acute mania that is associated with bipolar I disorder is thought to be mediated by antagonism at D2 and other monamine receptors. Additionally, olanzapine is postulated to produce its mood stabilizing and antidepressant effects through 5-HT2A receptor blockade and increased cortical DA and NE concentrations.114 Several studies have investigated the effect of olanzapine-induced weight gain and new-onset type 2 diabetes.115,116 In a comparison study with risperidone, olanzapine was shown to have a greater risk of producing dyslipidemia and type 2 diabetes.105,116

Quetiapine. Quetiapine, 2- [2-(4-dibenzo[b,f] [ 1,4]thi-azepin-11 -yl-1 -piperazinyl)ethoxy] -ethanol fumarate (2:1, salt) (Seroquel), is a white to off-white crystalline powder that is moderately water soluble. Quetiapine is rapidly absorbed, and peak plasma levels occur 1 to 2 hours after administration. Food does not appreciably affect the absorption of quetiapine. The compound is 83% bound to plasma proteins and it has a mean elimination half-life of 7 hours. Administration of a single dose of 14C-quetiapine showed that only 1% of the drug was excreted unchanged, with 73% excreted into the urine and approximately 30% excreted in the feces.23 Numerous metabolites of quetiapine are known, and the sulfoxide metabolite represents the major metabolite present in plasma (Fig. 13.10). This metabolite is pharmacologically inactive. The remaining metabolites represent only 5% of the total radioactivity found in plasma. The 7-hydroxy and the 7-hydroxy-n-desalkyl are active metabolites, but

2-hydroxymethyl metabolite

H S^ ^CH3 Olanzapine

A/-oxide metabolite

2-hydroxymethyl metabolite

Figure 13.9 • Metabolic pathway of olanzapine.

H S^ ^CH3 Olanzapine

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