Slow metabolizers

Encainide is almost completely absorbed from the GI tract. Eood may delay absorption without altering its bioavailabiUty. The dmg is rapidly metabolized in 90% of the patients to two principal metaboUtes, 0-demethylencainide (ODE) and 3-methoxy-O-demethylencainide (MODE), while the other 10% metabolize encainide slowly with Htde or no ODE or MODE formed. Encainide, ODE, and MODE are extensively protein bound 75—80% for encainide and ODE and 92% for MODE. Peak plasma concentrations are achieved in 30—90 min. Therapeutic plasma concentrations are very low the concentrations of ODE and MODE are approximately five times those of encainide. The findings with the metaboUtes are significant because ODE is 2—10 times and MODE, 1—4 times more effective than encainide as antiarrhythmics. The half-Hves for encainide in fast and slow metabolizers is 1—2 h and 6—12 h, respectively. The elimination half-life for ODE is 3—4 h and for MODE 6—12 h in fast metabolizers. Excretion occurs through the Hver and kidneys (1,2). 

CYP2D6 [polymorphisms] (MIM 124030) Slow metabolism of certain drugs (eg, debrisoquin), resulting in their accumulation... 

The pharmacokinetic profile of (16) and its two analogues were investigated in Sprague-Dawley rats. Removal of the metabolically labile tert-butyl group on the aryl moiety slowed metabolism and the rate of clearance. However, the overall half-life of (17a) was unaffected because of a lower volume of distribution. On the other hand, (17b) showed an increased half-life (ca. 3h versus 1 h) compared to (16) and (17a). While the oral bioavailability of (16) was negligible, (17a) and (17b) were better absorbed, with bioavailability values of 39% and 17%, respectively. While undoubtedly improved in terms of pharmacokinetics compared to (16), the bioactivity of (17a) and (17b) awaits validation in vivo. 

What causes "flashback" psychosis in some individuals who abstain from further PCP consumption following the initial dose Is it residual drug, slow metabolism to a new stable metabolite, or a "permanent" change in a defined portion of the CNS ... 

While generally not of major concern, omeprazole may inhibit the metabolism of warfarin, diazepam, and phenytoin lansoprazole may decrease theophylline concentrations. Drug interactions with omeprazole are of particular concern in patients who are considered slow metabolizers, as are approximately 3% of the Caucasian population. Unfortunately, it is unclear which patients have the polymorphic gene variation that makes them slow metabolizers.17 The metabolism of esomeprazole may also be altered in patients with this polymorphic gene variation. Patients on potentially interacting drugs should be monitored for development of drug-related problems. 

Conversely, the metabolism of divalproex can be increased by enzyme-inducing drugs such as carbamazepine and phenytoin, while divalproex may simultaneously slow metabolism of the other agents.35... 

This model is the most fitting for the non-metabolized or very slow metabolized organochlorines like dioxin or DDT. We can see that this is an additional step in understanding the dioxin bioaccumulation in ecosystems. 

These studies suggest that there are substance(s) in tobacco smoke, as yet unidentified, that inhibit the metabolism of nicotine. Because nicotine and cotinine are metabolized by the same enzyme, the possibility that cotinine might be responsible for the slowed metabolism of nicotine in smokers was examined. In a study in which nonsmokers received an intravenous infusion of nicotine with and without pretreatment with high doses of cotinine, there was no effect of cotinine on the clearance of nicotine (Zevin et al. 1997). Also, carbon monoxide at levels and in patterns similar to those experienced during smoking had no effect on nicotine and cotinine clearance (Benowitz and Jacob 2000). 

In summary, genotyping of CYP2C19 (25) may only be relevant in people of Asian extraction, of whom up to 20% may be slow metabolizers. In practice, one could also avoid the need to genotype by using a PPI with lower metabolism by CYP2C19 (e.g., rabeprazole). 

Half-life 10 to 32 hours in less than 10% of patients (slow metabolizers). 

The halflife of THC concentration ranges between 0.8 to 9.8 days. There is too much human variation to even approximate how long THC will be detected in the urine of an individual. Infrequent users with a fast metabolism will have the shortest detection time. Frequent users with a slow metabolism will have long detection times. The only way to estimate a detection time is to consider the lower and upper bounds (3-45 days), and decide based on the factors I ve mentioned. 

Furthermore, as already discussed, important ethnic variations exist in the metabolic activity of both CYP3A4 and 2D6 and caution is needed when administering buspirone to Asians who are more likely to be slow metabolizers of CYP2D6 substrates and may also be on other medications that further inhibit CYP2D6 activity. 

Geriatric Considerations - Summary One of the least likely antihistamines to cause CNS effects. No dose adjustments required in older adults with decreased renal function. Slow metabolizers likely to experience increased side effects and anticholinergic effects. Increased risk of sedation at higher doses. 

All SSRIs (e.g., Feonard et ah, 1997) and in particular fluoxetine, Fluvosamine and paroxetine are metabolized by hepatic cytochrome P450 enzymes. Therefore, it is important to be aware of the possibility that the therapeutic or toxic effects of other medications metabolized by the cytochrome P450 isoenzyme system can be increased. Substantial inhibition of these isoenzymes converts a normal metabolizer into a slow metabolizer with regard to this specific pathway. Inhibition of the hepatic oxidative isoenzymes has been associated with a reduction, to a varying extent, in the clearance of many therapeutic agents, including the TCAs, several neuroleptics, antiarrhythmics, theophy-lene, terfenadine, benzodiazepines, carbamazepine, and warfarin (for a complete list, see Nemeroff et ak, 1996). 

Some people are rapid metabolizers of drugs and some are slow metabolizers. Factors that can affect the response to drugs... 

While an individual s phenotype can directly assess a clinical measureable biologic function of interest (e.g., whether an individual is a fast or slow metabolizer of a certain drug), phenotyping is often expensive and not readily adapted for routine clinical practice. Analysis of genetic information—genotyping—might prove to be more efficient and better able to be adapted to the individualization of drug therapy. 

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