Dirithromycin

Description

Dirithromycin, an orally active oxazine derivative of erythromycin, is a secondgeneration macrolide antibiotic. It was first introduced in Spain for the treatment of respiratory tract, skin and soft tissue infections. It is safe and effective in treating acute bronchitis, acute bacterial exacerbation of chronic bronchitis, pneumonia, pharyngitis, and tonsillitis. Dirithromycin has been reported to have a similar antimicrobial spectrum and potency to erythromycin. However, compared to other macrolide antibiotics, dirithromycin has improved oral bioavailability, higher tissue permeability and longer duration of action. The once-daily therapy regiment is advantageous in terms of patient compliance and is a good alternative for patients who are unable to take penicillin.

Description

Dirithromycin is a macrolide antibiotic. It is a prodrug of erythromycylamine that has outstanding activity against Campylobacter. Dirithromycin is a group 3 agent with respect to its interaction with the cytochrome P450 (CYP) isoform 3A4, as it interferes poorly with CYP3A4 in vitro and generally does not alter drug metabolism in vivo.

Chemical properties

white crystals

Originator

Boehringer Ingelheim (Germany)

The Uses of Dirithromycin

Dirithromycin is a macrolide antibiotic pro-drug of 9S-erythromycylamine, a close analogue of erythromycin in which the 9-keto group is replaced with an amino group in the S-configuration. Although erythromycylamine overcomes the acid instability of erythromycin, it is poorly absorbed following oral administration. Dirithromycin is formed by reacting erythromycylamine with an aldehyde to form a Schiff base which undergoes cyclisation to an oxazine with the C11-alcohol. Dirithromycin provides higher tissue levels and prolonged in vivo half-life by slowly releasing erythromycylamine.

The Uses of Dirithromycin

Semi-synthetic derivative of Erythromycin. Antibacterial

The Uses of Dirithromycin

antihypertensive

What are the applications of Application

Dirithromycin is a semi-synthetic derivative of Erythromycin that acts as an antibacterial

Definition

ChEBI: The hemi-aminal resulting from the condensation of the erythromycin derivative (9S)-erythromycyclamine with 2-(2-methoxyethoxy)acetaldehyde. As the oxazine ring containing the hemi-aminal group is unstable under both acidic and alkaline co ditions, dirithromycin functions as a more lipid-soluble prodrug for (9S)-erythromycyclamine. Administered as enteric coated tablets to protect it from acid catalysed hydrolysis in the stomach, it is used to treat respiratory tract, skin, nd soft tissue infections caused by susceptible organisms.

Manufacturing Process

The reactions were conducted for the synthesis of dirithromycin according to the following procedure. 2-(2-Methoxyethoxy)acetaldehyde dimethyl acetal (12 g, 2.7 eq) was placed in a three-neck flask equipped with a mechanical stirrer and dissolved in 60 ml of acetonitrile containing 4% water. pToluenesulfonic acid (200 mg, 0.04 eq) was added and the mixture was stirred under a nitrogen atmosphere for 3 hours at 30°C, after which, the temperature was adjusted to 23°C.
Erythromycylamine (20 g, 1 eq) was added over a 20 minute period and stirring continued for 12-16 hours at 23°C. The reaction mixture was cooled to 0°C for 2 hours and then filtered to recover dirithromycin crystals. The crystals were washed with cold acetonitrile and dryed in vacuo at 40°C. Theyield of final product was 84.5% with a potency of 95.4% (average of three reactions). Crystalline dirithromycin a condensation product of 2-(2- methoxyethoxy)acetaldehyde dimethyl acetal and erythromycylamine.

brand name

Dynabac (Lilly);Nortron.

Therapeutic Function

Antibacterial

General Description

The incidence and severity of GI adverse effects associatedwith dirithromycin are similar to those seen with oralerythromycin. Preliminary studies indicate that dirithromycinand erythromycyclamine do not interact significantly with cytochromeP450 oxygenases. Thus, the likelihood of interferencein the oxidative metabolism of drugs such as phenytoin,theophylline, and cyclosporine by these enzymes may be lesswith dirithromycin than with erythromycin. Dirithromycin isrecommended as an alternative to erythromycin for the treatmentof bacterial infections of the upper and lower respiratorytracts, such as pharyngitis, tonsillitis, bronchitis, and pneumonia,and for bacterial infections of other soft tissues and theskin. The once-daily dosing schedule for dirithromycin is advantageousin terms of better patient compliance. Its place intherapy remains to be fully assessed.

Pharmaceutical Applications

A prodrug of erythromycylamine, a semisynthetic erythromycin A derivative, formulated for oral administration. Activity against respiratory pathogens is generally poorer than that of erythromycin A.
The long apparent elimination half-life (30–44 h) allows once-daily administration. Around 60–90% of a dose is converted to erythromycylamine within 35 min after intravenous administration. After oral administration of single doses of 500–1000 mg to healthy volunteers, the peak plasma concentrations ranged from 0.29 to 0.64 mg/L after 4–5 h. The absolute bioavailability after oral administration is about 10%. It achieves a higher concentration than erythromycin in some tissues. After a 500 mg single oral dose, the mean peak biliary concentration was 139 mg/L. Renal and non-renal clearance was lower in patients with biliary disease than in other patients or healthy volunteers.
About 60–80% of an oral dose and over 80% of an intravenous dose are eliminated in the feces, predominantly as erythromycylamine. Dosage adjustments do not appear necessary in patients with mild or moderate hepatic, biliary or renal impairment. Negligible amounts of the drug are removed during hemodialysis.
Adverse events are similar to those found with other macrolides. Gastrointestinal events are most common; around 5% of patients experience abdominal pain, diarrhea or nausea.
It has been used in community-acquired infections of the respiratory tract and skin and soft-tissue infections. It is no longer widely available.