Liver drug interactions

Following concurrent administration of two drugs, especially when they are metabolized by the same enzyme in the liver or small intestine, the metabolism of one or both drugs can be inhibited, which may lead to elevated plasma concentrations of the dtug(s), and increased pharmacological effects. The types of enzyme inhibition include reversible inhibition, such as competitive or non-competitive inhibition, and irreversible inhibition, such as mechanism-based inhibition. The clinically important examples of drug interactions involving the inhibition of metabolic enzymes are listed in Table 1 [1,4]. 

Tacrine is particularly damaging to the liver and can result in hepatotoxicity. Because tacrine is more likely to cause adverse reactions and drug interactions, it must be administered more frequently (4 times a day) and is rarely used in current therapy. Donepezil has fewer and milder side effects than tacrine It is considered the agent of first choice However, some patients may achieve a better response with one drug than another. Additional adverse reactions are listed in the Summary Drug Table Cholinesterase Inhibitors. 

Use of zileuton is uncommon due to the need for dosing four times a day, potential drug interactions, and the potential for hepatotoxicity with the resulting need for frequent monitoring of liver enzymes. In patients started on zileuton, serum alanine aminotransferase concentrations should be monitored before treatment begins, monthly for the first 3 months, every 2 to 3 months for the remainder of the first year, and then periodically thereafter for as long as the patient continues to receive the medication. Zileuton also inhibits the cytochrome P-450 (CYP) mixed function enzyme system and has been shown to decrease the clearance of theophylline, R-warfarin and propranolol.34... 

Ethinyl estradiol is metabolized in the liver via the cytochrome P-450 system. It is metabolized primarily via CYP450 3A4. When reviewing drug interactions of oral contraceptives, it is important to keep in mind that antibiotic administration during contraceptive use may decrease the efficacy of many combined contraceptives. Refer to Table 45-4 for a list of common drug interactions seen with oral contraceptives.1,31... 

Black cohosh has been one of the most studied herbal remedies for vasomotor symptoms, and it has not demonstrated a substantial benefit over placebo. The mechanism of action, safety profile, drug-drug interactions, and adverse effects of black cohosh remain unknown. In non-placebo-controlled trials conducted for 6 months or less, black cohosh demonstrated a small reduction in vasomotor symptoms. It has not been shown to be effective for vasomotor symptoms in women with breast cancer.33 There have been case reports of hepatotoxicity with the use of black cohosh.36 Caution should be exercised when considering the use of this product, especially in patients with liver dysfunction. 

Many experts now consider voriconazole as the initial drug of choice for invasive aspergillosis in patients without significant contraindications (e.g., drug interactions or preexisting liver dysfunction) to azole therapy. 

The patient may be failing his current regimen due to nonadherence or a drug interaction with famotidine. Check HIV RNA and CD4 count to evaluate HIV treatment efficacy and complete blood count with differential, chemistry profile, and liver function tests for routine follow-up. 

Xia XY, Peng RX, Yu JP, Wang H, Wang J (2002) In vitro metabolic characteristics of cytochrome P-450 2A6 in Chinese liver microsomes. Acta Pharmacol Sin 23(5) 471-476 Zevin S, Benowitz NL (1999) Drug interactions with tobacco smoking. An update. Clin Pharma-cokinet 36(6) 425 38... 

Drug Interactions. No modern discussion of the history of antidepressants would be complete without mention of the debate regarding potential drug interactions. As discussed more fully in Chapter 2, medications may interact in several ways, and their interactions may be helpful or harmful. The antidepressant debate has focused on the way these drugs influence the liver s ability to metabolize and thus deactivate other drugs. In particular, it is the impact of antidepressants on the liver s cytochrome P450 family of enzymes that has been so extensively discussed. 

Drug-drug interactions are often more problematic with carbamazepine than other mood stabilizers. Carbamazepine increases the activity of certain liver enzymes. Because these enzymes metabolize and eliminate medications and other substances introduced to the body, carbamazepine therapy can decrease the blood level and thereby reduce the effectiveness of itself (a phenomenon called autoinduction) and other medications that are metabolized by these enzymes. It is not unusual to find that the dose of carbamazepine must be increased after several weeks, because it has increased its own elimination. Other medications may likewise be less effective. Of particular concern are the oral contraceptives, Depo-Provera, and protease inhibitors used for the treatment of HI V+ patients. Oral contraceptives often require an increase in dose. 

From these results it can be concluded that liver slices are a powerful tool for studying the mechanisms and specificity of carrier-mediated uptake of drugs and drug interactions which occur at the transport level. 

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