Tilidine (Valoron (R) N)

Tilidine is a drug that is used for a variety of purposes, but the most common is as a topical analgesic. It is also known to help with gastrointestinal disorders, such as nausea and vomiting. This drug is also used in the treatment of asthma and other respiratory illnesses.

Indications

Tilidine is a prodrug with a weak opioid effect. It is commonly used for analgesia and restless legs syndrome in Germany. In combination with naloxone it is claimed to prevent opiate dependence. However, it can also have undesirable side effects. For example, it can cause nausea, dizziness, and constipation.

Although Tilidine has a high analgesic efficacy, it can be associated with unwanted side effects. The risk of hypotension, CNS depression, and other adverse effects may be increased when used in combination with other substances.

Tilidine has a high first-pass metabolism, which means it is rapidly metabolised in the gut. CYP3A4 inhibitors may inhibit this step. Also, the presence of a CYP2C19 gene variant can result in ultrarapid metabolism.

Tilidine is available in fixed combinations with naloxone, which are prescribed orally. These combination products are contraindicated in patients with severe liver dysfunction.

To investigate the pharmacokinetics of naloxone, an open-label, single-dose study was performed in 8 patients with severe cirrhosis of the liver. Participants were selected based on eligibility and Child-Pugh score. They received a naloxone dose of 4 mg.

Pharmacokinetics

Tilidine (Valoron (r) N) is an opioid analgesic that is used in the treatment of moderate-severe pain. It contains the opiate antagonist naloxone. Naloxone acts as a central depressant and suppresses pain perception and transmission.

Tilidine is administered intravenously in doses of up to 400 milligrams. Its pharmacokinetics are characterized by rapid absorption and metabolism in the liver. The drug is rapidly converted to nortilidine. However, the analgesic activity of the drug is mainly due to nortilidine.

Nortilidine is metabolised by the same CYP isozymes as the prodrug Tilidine. According to Michaelis-Menten kinetics, it is eliminated through the N-demethylation pathway. The elimination half-life of nortilidine is the lowest of all the Tilidine metabolites.

In this study, pharmacokinetic parameters of norTilidine were studied in healthy male volunteers. Blood samples were taken for 28 hours. There were no significant changes in the total naloxone and norTilidine levels.

Oral quinidine, a CYP3A4 inhibitor, did not affect the pharmacokinetics of norTilidine. A 600 mg oral dose of quinidine significantly increased the oral morphine Cmax by 88%.

CYP3A4

A large number of inhibitors are currently available for CYP3A4 inhibition. These include ritonavir, naloxone and efavirenz. Although they can be used in combination with tilidine, they may have clinically important interactions. Therefore, understanding tilidine’s metabolism is crucial to rational pain therapy.

The pharmacokinetics of tilidine in healthy volunteers were investigated. Tilidine was administered orally at a dose of 100 mg, followed by naloxone (4.0 mg) and efavirenz (300 mg). NorTilidine, a metabolite of tilidine, was measured by noncompartmental analysis.

In order to calculate the metabolic clearance of tilidine, data from published in vivo studies were incorporated. The tilidine pharmacokinetic parameters were calculated using the Analyst version 1.4.2 software.

The study was conducted on 12 healthy volunteers. Each volunteer received tilidine (100 mg) and efavirenz (300mg) twice daily for three days. Blood samples were taken at 0, 24, and 72 hours. Quality control samples were also measured. They were analyzed in duplicate.

The tilidine pharmacokinetics in CYP2C19 ultrarapid metabolizers were compared to those in healthy volunteers. This was performed by Wilcoxon matched pairs signed rank test. None of the tilidine pharmacokinetics were significantly different for CYP2C19 genotypes.

Metabolism

Tilidine is an opioid analgesic used for the relief of moderate pain. It has a half-life of 3-5 hours and a duration of action of 4-6 hours. A small amount is excreted in the urine. Almost all of the analgesic effect is exerted by nortilidine, the active metabolite of tilidine.

Nortilidine is formed from tilidine during the first-pass metabolism of the drug in the liver. This is a rate-limiting step of the tilidine metabolism. Inhibitors of CYP2C19 have been shown to inhibit nortilidine formation. However, it is not known whether inhibition of CYP2C19 has a clinically relevant effect on the pharmacokinetics of tilidine.

To evaluate the effect of CYP2C19 inhibition on tilidine metabolism, the pharmacokinetics of tilidine were compared between CYP2C19-inhibiting drugs and placebo. Data were obtained after a single intravenous administration of 50 mg tilidine. The mean Cmax and AUC of bisnortilidine were not significantly different between the two groups.

The pharmacokinetics of tilidine did not change after dialysis. The amount of tilidine excreted in the urine was 13.9 +- 5.9%.