Piperine which inhibits cyp3a4

Planta Med. Effect of piperine on the steady-state pharmacokinetics of phenytoin in patients with epilepsy. The influence of piperine on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate, in healthy volunteers. Eur J Clin Pharmacol. Effect of piperine on CYP2E1 enzyme activity of chlorzoxazone in healthy volunteers. Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers.

For an electronic version of this article, including references, visithanstenandhorn. Piperine Drug Interactions. July 28, John R. John's wort are important agents modifying drug metabolism and transport and thereby contribute to interindividual variability in drug disposition. Preliminary data indicate that piperine, a major component of black pepper, inhibits drug-metabolizing enzymes in rodents and increases plasma concentrations of several drugs, including P-glycoprotein substrates phenytoin and rifampin in humans.

We therefore investigated the influence of piperine on P-glycoprotein-mediated, polarized transport of digoxin and cyclosporine in monolayers of Caco-2 cells. For this reason, it could be said that piperine may decrease metabolism of midazolam. Bayesian predicted thin line and observed symbols plasma midazolam concentrations in placebo A and piperine B receiving groups. Note the different scales of concentrations in the figures.

The population plasma midazolam concentrations time curves in placebo A and piperine B treatment groups are shown in Figure 4. Based on the figure A , one subject showed an out of range concentration at the time of 2.

It is considered that the maximum concentration in placebo group occurred at 1. Our results can demonstrate a possible relation between midazolam concentration and CYP3A activity. This enzyme has an important role in microsomal drug metabolisms. Thirty percent of cytochrome P enzymes of liver are made of CY3A4 [ 19 ].

It has been estimated that CYP3A4 is responsible for 50 percent of the metabolism of all drugs that being eliminated via hepatic microsomal enzymatic system [ 20 , 21 ]. In addition to having an active role in hepatic metabolism of drugs, CYP3A4 is sufficiently active in the small intestine [ 22 , 23 ]. CYP3A4 is active in the metabolism of lipophilic substrates such as fentanyl, alfentanil, oxycodone, and methadone [ 24 — 28 ].

CYP3A4 inhibitors that have been well studied include: azole antifungal agents and a number of the macrolide antibodies [ 29 ]. There are clinically important examples such as midazolam, alprozolam, atorvastatin, simvastatin, felodipine, nifedipine, and cyclosporine that are affected by this system [ 29 ].

The metabolism of intravenous midazolam can reflect to the rate of hepatic CYP3A activity but when it is administered by mouth, the metabolism can demonstrate both liver and enteral origin of CYP3A [ 22 , 23 ]. Any changes in CYP3A enzymatic pathway, may affect midazolam metabolism. CYP3A activity can be affected by different factors such as genetics, nutritional, environmental, and hormonal and disease conditions.

These variations in CYP3A activity may create some problems in dosing of the drugs those are metabolized by this enzymatic system. These variations may increase drug interaction episodes and cause side effects to the patients. In the present study piperine the main alkaloid of black pepper [ 7 ], could significantly prolong life time of midazolam in body.

This may increase the pharmacologic activity and can induce and prolong sedative-hypnotic properties of the drug. These effects of piperine may be the result of inhibition of CYP3A4 activity. Previous animal studies have demonstrated that piperine inhibits several CYP mediated pathways [ 30 ]. Piperine is a selective non-competitive inhibitor of CYP3A but has lower activity on the other microsomal enzymes.

It can inhibit activity UDP-glucuronosyl transferase as well [ 31 , 32 ]. Pretreatment of piperine in mice induced higher plasma levels of theophylline, rifampin, phenytoin and propranolol and QCoA compared to control [ 33 , 34 ]. Such an effect has been reported in a previous clinical study [ 15 ].

It has been reported that a single dose of 1 g of black pepper can increase the AUC area under the curve of plasma concentration-time of phenytoin [ 14 ]. This may increase duration and severity of side effects of subject drugs substrate of CYP3A following their elevated plasma levels. As we already showed the midazolam side effects in piperine pretreated subjects were considerable compared to placebo.

The inhibition or induction of enteral CYP3A4 and p-glycoprotein can mediate considerable drug interactions. These of interactions may be due to a considerable variation in drug action from no effect to toxic effect of drugs [ 35 — 38 ]. The genes of CYP3A4 and p-glycoprotein are expressed in enterocytes and the bioavailability of many drugs such as cyclosporine A, midazolam, verapamil, HIV protease inhibitors and digoxin could be affected by the enzyme and transporter [ 11 , 36 , 38 — 40 ].

Metabolism of midazolam when prescribed intravenously shows the activity of hepatic CYP3A, but when it is prescribed orally, it can show the activity of both hepatic and intestinal CYP3A [ 41 , 42 ]. After oxidative metabolism, midazolam changes into one of its main metabolites, hydroxide midazolam, in liver, and is mediated in an exceptional rout by CYP3A isoforms [ 43 , 44 ].

Piperine inhibits p-glycoprotein and CYP3A activity. Since, these proteins become expressed in enterocytes and hepatocytes; they have an effective role in first-pass metabolism of subject drugs. Piperine content of nutritional regimen can change the levels of p-glycoprotein and CYP3A substrates in blood when those administered by mouth [ 45 ].

However more researches are needed to prove intestinal or hepatic effects of piperine, especially to justify their mechanism in the present study. In this investigation duration of sedation and possible hypnosis action of midazolam in females was longer than the males. This may be to the result from higher plasma level of midazolam after piperine pretreatment in female subjects.

Perhaps, it is concluded that sex may be an important factor to obtaining plasma concentration of midazolam. This may be due to higher activity of CYP3A4 in female at normal condition compared to male [ 46 — 49 ]. In a previous phenotyping study by the authors, similar results by sex variability on CYP3A activity has been reported [ 17 ]. For this reason more clinical effects are expected in females if the enzyme becomes inhibited.

This may predispose patients to demonstrate unexpected drug manifestations compared to normal subjects. According to the present investigation, piperine may inhibit CYP3A4 activity and increase the level of midazolam as a substrate of the enzyme. Evans AM: Influence of dietary components on the gastrointestinal metabolism and transport of drugs.

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