Ziprasidone metabolism

Beedham, C., Miceli, J. J. Obach, R. S. (2003). Ziprasidone metabolism, aldehyde oxidase, and clinical implications. J. Clin. Psychopharmacol, 23, 229-32. 

They have large volumes of distribution and are largely metabolized through the cytochrome P450 pathways (except ziprasidone). 

This group includes risperidone, quetiapine, olanzapine, ziprasidone, and aripiprazole. But all these agents cause dose-related EPS and appear in general more likely to cause diabetes and other metabolic problems than some of the older drugs (see Duggan et ah, 2005). 

Cardiovascular side effects. Ziprasidone produced a mean QTc prolongation of 21 ms at maximal blood levels achieved with typical therapeutic doses. However, in all clinical trials, the rate of QTc intervals greater than 500 ms (considered a threshold for arrhythmia risk) did not differ from the rate associated with placebo (<0.1%). The QTc effect of ziprasidone is larger than that of other atypical antipsychotics but smaller than that of thioridazine. Blood levels of ziprasidone increased about 40% when ketoconazole (a metabolic inhibitor) was coadministered, and no change in QTc duration was detected. 

Drugs that inhibit CYP 3A4 reduce metabolism of ziprasidone concurrent treatment with ketoconazole increased blood levels of ziprasidone by approximately 40%. Carbamazepine (and possibly other enzyme inducers) may decrease ziprasidone levels by approximately 35%. Effects of ziprasidone on metabolism of other drugs have not been reported. 

Pfizer has also prepared both and " C-labelled ziprasidone (Schemes 18 and 19) to detennine its metabolism and tissue distnbution. It was envisioned that tritium could be introduced in the last step of e synthesis utilizing the selective replacement of a bromine atom on the benzisothiazole nng. Therefore, the synthesis began with the bromination of 39 using bromine in acetic acid with FeCls catalysis. The dibrominated regioisomer 60 was isolated by liquid chromatography in 18% yield and reacted with... 

The effects of neuroleptic drugs on serum lipids in adults have been reviewed (439). Haloperidol and the atypical neuroleptic drugs ziprasidone, risperidone, and aripipra-zole, are associated with lower risks of hyperlipidemia, whereas chlorpromazine, thioridazine, and the atypical drugs quetiapine, olanzapine, and clozapine are associated with higher risks. Treatment of the metabolic disturbances caused by neuroleptic drugs has also been reviewed (440). 

Although no special precautions are suggested when ziprasidone is co-prescribed with metabolic inhibitors, drugs that do not inhibit hepatic enzymes should be preferred. 

Ziprasidone is oxidatively metabolized by CYP3A4, but it does not inhibit CYP3A4 or other isoenzymes at clinically relevant concentrations. The effect of ketoconazole 400 mg qds for 6 days on the single-dose pharmacokinetics of ziprasidone 40 mg has been evaluated in an open, placebo-controlled, crossover study in healthy volunteers... 

The atypical antipsychotic drug ziprasidone (105)(514) was approved for the treatment of schizophrenia in the United States in early 2001. Studies of the biotransformation of this benzoisothiazolederivative reveal that it is extensively metabolized in rats (515,516) and in... 

Metabolites apparently do not contribute to the pharmacological activity of ziprasidone in vivo because the sulfone and sulfoxide metabolites exhibit low affinities at 5-HT, and D2 receptors (517). Limited investigations of cytochrome P450 isoforms responsible for the primary oxidative metabolic reactions for ziprasidone indicate a major role for CYP3A4 oxidation to the sulfone, shown by Prakash et al. (518), and virtually no role for CYP2D6 (518,519). 

A study with the potent CYP 3 A4 inhibitor ketoconazole showed minimal effects on ziprasidone single-dose pharmacokinetics, with only a 33% mean increase in the ziprasidone area under the time-versus-concentration curve. " These results are consistent with data suggesting that aldehyde oxidase is the major metabolic pathway for ziprasidone, with only 30% to 35% being metabolized by CYP 3A4. ... 

AO and XO are cytosolic enzymes and are closely related. However, they differ in their substrate/inhibitor specificities. AO is involved in the metabolism of several clinically significant drugs such as famciclovir, zaleplon, zonisamide, and ziprasidone [69-72], XO has a narrower substrate specificity than AO and is mainly active toward purines and pyrimidines. XO plays a role in the oxidation of several chemotherapeutic agents and has been implicated in the bioactivation of mitomycin B [73]. 

Kamel, A., Prakash, C., and Obach, S. (2002) Determination of the enzyme involved in the reductive metabolism of ziprasidone to dihydroziprasidone and the formation of S-methyl dihydroziprasidone using human in vitro systems and electrospray ionization tandem mass spectrometry. Proceedings of the 50th ASMS Conference, Orlando, USA. 

Prakash, C., Kamel, A., Gummerus, J., and Wilner, K. (1997) Metabolism and excretion of the antipsychotic drug, ziprasidone, in humans. Drug Metab. Dispos. 25, 863-872. 

In a placebo-controlled, crossover study, 18 women taking an oral contraceptive (ethinylestradiol/levonorgestrei 30/150 micrograms) for at least 3 months were also given ziprasidone 20 mg twice daily for 8 days. The only change in the pharmacokinetics of the two steroids was an approximately 30-minute increase in the time to maximum plasma concentration of the levonorgestrel, but this was not considered to be clinically significant. No adverse effects occurred. It was concluded that combined use is safe and that ziprasidone does not affect the efficacy of this oral contraceptive and is also unlikely to affect the metabolism and therefore effieaey of other similar contraceptives. 

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