Fluoxetine liver

Liu, Z. Q., Shu, Y., Huang, S. L. et al. (2001). Effects of CYP2C19 genotype and CYP2C9 on fluoxetine N-demethylation in human liver microsomes. Acta Pharmacologica Sinica, 22 85-90. 

Liu Z-Q, Tan Z-R, Wang D, Huang S-L, Wang L-S, et al. 2002. Simultaneous determination of fluoxetine and its metabolite p-trifluoromethylphenol in human liver microsomes using a gas chromatographic-electron-capture detection procedure. J Chromatogr B 769 305. 

Diphenhydramine, diltiazem, carbamazepine and norfluoxetine have been reported simultaneously in the same wild fish [107]. Moreover, diclofenac was found accumulating in vultures [119], fluoxetine, sertraline and the SSRl metabolites norfluoxetine and desmethylsertraUne were detected in fish [120]. Diclofenac bioaccumulation factors were 10-2,700 in the liver of fish and 5-1,000 in the kidney, depending on exposure concentrations [40, 121]. Gemfibrozil occurred in blood plasma of goldfish after exposure over 14 days at 113 times higher levels than in water [40]. 

Most benzodiazepines undergo oxidative metabolism in the liver that may be enhanced by enzyme inducers (e.g. carbamazepine, phenytoin) or slowed by inhibitors (sodium valproate, fluoxetine, fluvoxamine). Oxazepam, lorazepam and temazepam are directly conjugated and are not subject to these interactions. 

When drugs are administered orally, they typically are absorbed in the small bowel, enter the portal circulation, and pass through the liver. Both CYP enzymes in the bowel wall and in the hepatocytes can metabolize a fraction of the drug before it reaches the systematic circulation (i.e., first-pass metabolism or first-pass effect). The extent of this effect can be broadly altered by diseases (e.g., cirrhosis, portacaval shunting, persistent hepatitis, congestive heart failure), and by some drugs (e.g., alcohol, ketaconazole, fluoxetine) influencing the peak concentrations achieved and the ratio of the parent compound to metabolites ( 11, 19, 20). 

The drug has a half-life of 6-8 hours. It is extensively metabolized in the liver, and stereoselective metabolism of its two isomers is observed. Since metabolism of ( R)-carvedilol is influenced by polymorphisms in CYP2D6 activity and by drugs that inhibit this enzyme s activity (such as quinidine and fluoxetine, see Chapter 4), drug interactions may occur. Carvedilol also appears to attenuate oxygen free radical-initiated lipid peroxidation and to inhibit vascular smooth muscle mitogenesis independently of adrenoceptor blockade. These effects may contribute to the clinical benefits of the drug in chronic heart failure (see Chapter 13). 

Dextromethorphan is known to interact with quini-dine and terbinafine. In both cases, there is a reduction in the metabolism of dextromethorphan by the liver. Terbinafine is a drug used to treat fungal infections. Quinidine is used for the treatment of malarial infections and heart rhythm problems. There has been a case report of a drug interaction between the use of fluoxetine (Prozac) and dextromethorphan. Fluoxetine is an antidepressant in the class of drugs called serotonin reuptake inhibitors. 

These selective serotonin reuptake inhibitors (SSRIs) include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), citalopram (Celexa), and, most recently, escitalopram (Lexapro see the appendix). These drugs block the removal of the neurotransmitter serotonin from the synaptic cleft. A number of other antidepressants are potent nonselective serotonin reuptake inhibitors (NSRIs). These include the atypical venlafaxine (Effexor) and the tricyclic clomipramine (Anafra-nil). Nefazodone (Serzone) has been withdrawn from the market due to liver damage. 

The time course of the raised aspartate transaminase and its resolution in response to citalopram withdrawal suggests that citalopram was responsible for the hepatic damage in this case. The earlier exposure to fluoxetine did not apparently cause liver damage, suggesting that the response to citalopram did not involve blockade of serotonin re-uptake. 

In a post-marketing surveillance study there were some cases in which fluoxetine alone appeared to have precipitated hepatitis, which remitted when treatment was withdrawn (27). Fluoxetine can cause mild increases in liver enzymes, with a rate in clinical trials of about 0.5%. Rarely this can progress to hepatitis. 

In an in vitro study of midazolam biotransformation using human liver microsomes, midazolam metabolism was competitively inhibited by the antifungal azoles keto-conazole, itraconazole, and fluconazole, and the antidepressant fluoxetine and its metabolite norfluoxetine (55). The degree of inhibition was consistent with the inhibition reported in pharmacokinetic studies, and suggests that in vitro assay is useful for predicting significant interactions. 

If, following absorption, medications were undisturbed by the body, we would need to take only one dose for an eternal effect. Of course, this is not the case. As soon as drugs enter the bloodstream, the process of metabolism ensues. The body recognizes the drug as a foreign substance and eliminates it outright (say, via the kidneys, as in the case of lithium) or transforms it chemically, using a complex enzyme mechanism located in the liver. This chemical transformation enables the medication to be eliminated from the body. In some cases, the chemical transformation produces a new compound that may also have therapeutic effects (or, in some rare instances, a toxic effect). For example, fluoxetine (trade name Prozac) is transformed into norfluoxetine, which is also an antidepressant. A similar situation occurs with the old tricyclic antidepressants (amitriptyline—trade name Elavil—to nortriptyline the latter, in fact, is... 

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