What Are P450 Inhibitors?

The enzymes involved in drug metabolism are mainly cytochrome P450 (CYP450). Drugs as inhibitors of CYP450 can weaken drug enzyme activity, slow down metabolism of itself or other drugs, and explain 70% of drug metabolic interactions. In most cases, the pharmacological activity of the target drug is enhanced, and even toxic side effects occur.

Liver drug inhibitor

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The enzymes involved in drug metabolism are mainly cytochrome P450 (CYP450). Drugs as inhibitors of CYP450 can weaken drug enzyme activity, slow down metabolism of itself or other drugs, and explain 70% of drug metabolic interactions. In most cases, the pharmacological activity of the target drug is enhanced, and even toxic side effects occur.

Chinese name

Liver drug inhibitor

Nature

Important metabolic enzymes

Features

Substrate metabolism slows and plasma concentration increases

Function

Reduced metabolic activity of CYP450 enzyme

Liver drug inhibitors mainly refer to a class of drugs (or foods) that can reduce the metabolic activity of CYP450 enzymes, make substrate metabolism slow, blood drug concentrations rise, and cause accumulation in the body.

Inhibitor types:

1. CYP1A2 inhibitors: CYP1A2 inhibitors mainly include antidepressant fluvoxamine, quinolone antibiotics and non-selective liver drug enzyme inhibitor cimetidine, etc., due to theophylline, warfarin, caffeine and other drugs Safety is low, and drug inhibitors can slow down the increase in adverse reactions with the metabolism of these drugs. Fluvoxamine combined with warfarin increased blood concentration by 65%, prolonged prothrombin time; enoxacin and warfarin increased bleeding risk; roxithromycin / azithromycin and warfarin significantly enhanced warfarin The anticoagulant effect of the forest, the INR was significantly higher after 4 to 7 days of combined use than that before the combined use; the combination of ciprofloxacin and theophylline can cause excessive central nervous system excitement.

2. CYP2C9 inhibitors: The inhibitors of CYP2C9 are mainly amiodarone, cimetidine, fluconazole, fluvastatin, isoniazid, etc. Warfarin is a substrate of multiple CYP450, there are two isomers, namely S-warfarin and R-warfarin, S-warfarin is 5 times more active than R-warfarin, and S-warfarin Farin is mainly metabolized by CYP2C9, so CYP2C9 inhibitors have a more significant effect on the anticoagulant activity of warfarin. Among the CYP2C9 inhibitors, amiodarone and fluconazole are commonly used drugs in the clinic. At present, there have been many reports about the significant prolongation of INR caused by the combination of amiodarone or fluconazole and warfarin. In a 1-year observation of 43 patients taking warfarin and amiodarone, it was found that the peak period of the interaction between the two drugs was the seventh week of combined use. The average maximum reduction of warfarin was 44%. When the maintenance dose is 400, 300, 200, or 100 mg, the daily dose reduction of warfarin is 40%, 35%, 30%, and 25%, respectively. In clinical use, PT and INR should be tested to adjust the dose.

3. CYP2C19 inhibitors, such as voriconazole and omeprazole, and its inducers include phenytoin sodium and rifampicin. Phenytoin sodium has a strong induction effect on CYP2C19 enzyme, which will have a significant effect on clinical medication. Voriconazole is not only a substrate of CYP2C19, 2C9, 3A4, but also its inhibitor, and has the strongest affinity for CYP2C19.

4. CYP2D6 is the only active CYP2D subfamily enzyme in humans, accounting for 4% of the total, but its drugs involved in metabolism account for 30% of the total CYP450 metabolizing drugs. The drugs metabolized by it are not only the antipsychotics and antidepressants metabolized by CYP450, but also some analgesics, such as codeine and tramadol, and beta-blockers such as metoprolol, card Verdilo et al. The characteristic of CYP2D6 enzyme is that its activity is not induced by chemicals, but can be inhibited. Its inhibitors include fluvastatin, fluvoxamine, quinidine, and fluoxetine, among which quinidine is the strongest inhibitor of CYP2D6.

5. CYP3A4 CYP3A4 is the enzyme with the most metabolizing drugs in CYP450, accounting for 50% of the total CYP450 metabolizing drugs, and its substrate coverage is extremely wide.

5.1 Macrolide antibiotics themselves are substrates of CYP3A4. After metabolism by the liver, the products of the macrolide antibiotics form a nitrosoalkane complex with the ferrous iron in CYP3A4 to inactivate the enzyme. This inhibitory effect on the enzyme is called suicide inhibition. 14-ring erythromycin and clarithromycin had the strongest inhibitory effects, followed by 16-ring josamycin and acetylspiramycin, and 15-ring azithromycin had almost no inhibitory effect.

5.2 Efavirenz has both an induction and an inhibitory effect on CYP3A4, and ritonavir is a strong inhibitor of CYP3A4. Both itraconazole and ketoconazole are strong inhibitors of CYP3A4. Care should be taken to check the drug concentration when combined with its substrate, and adjust the dose if necessary.

5.3 Among the calcium antagonists, diltiazem, nicardipine, verapamil, and mepiladil have an inhibitory effect on CYP3A4. Among them, mebendil is a potent drug enzyme inhibitor, at least Adverse reactions with more than 20 drugs such as astemizole, terfenadine, and cisapride.

5.4 Grapefruit is a tropical fruit and a moderate-acting inhibitor of CYP3A4. Studies have shown that grapefruit juice can affect the metabolism of dihydropyridine calcium antagonists such as felodipine, immunosuppressants such as cyclosporine A, and HMG-CoA reductase inhibitors such as simvastatin, atorvastatin, etc. Many active ingredients in grapefruit juice have a long half-life. You should stop taking grapefruit juice before using drugs metabolized by CYP3A4, and you cannot drink grapefruit juice immediately after stopping the medicine. You should consider several half-lives of each drug before Drinkable. ^[1]