Hepatotoxicity erythromycin

Hepatotoxicity- Erythromycin administration has been associated with the infrequent occurrence of cholestatic hepatitis. This effect is most common with erythromycin estolate. 

Hepatic - Hepatotoxicity is most commonly associated with erythromycin estolate. 

Cholestatic hepatitis may occur when drug therapy lasts longer than 10 days or repeated courses are prescribed. The hepatitis is characterized by fever, enlarged and tender liver, hyperbilirubinemia, dark urine, eosinophilia, elevated serum bilirubin, and elevated transaminase levels. Hepatitis has been associated with the estolate salt of erythromycin but not with other formulations. Although the hepatitis usually occurs 10 to 20 days after the initiation of therapy, it can occur within hours in a patient who has had such a reaction in the past. The hepatitis is believed to be the result of both a hepatotoxic effect and a hypersensitivity reaction this latter effect is reversible on withdrawal of the drug. Erythromycin and derivatives induce hepatic microsomal enzymes and interfere with the actions of various drugs, including theophylline and carbamazepine. 

Erythromycin Prevents bacterial protein synthesis by binding to the 50S ribosomal subunit Bacteriostatic activity against susceptible bacteria Community-acquired pneumonia t pertussis corynebacterial, and chlamydial infections Oral, IV hepatic clearance (half-life 1.5 h) dosed every 6 h cytochrome P450 inhibitor Toxicity Gastrointestinal upset, hepatotoxicity, QTC prolongation... 

Cholestatic hepatitis, which is associated primarily with erjdhromycin estolate, can be caused by all forms of erythromycin, including the base, estolate, ethylsuccinate, propionate, and stearate (39,41). Although it was originally speculated that a hypersensitivity reaction to the estolate ester rather than to the erjdhromycin itself was responsible for this adverse reaction (42), erythromycin does inhibit bile flow (43). Most probably the differences in hepatotoxicity between the various erythromycin derivatives are of a quantitative rather than a qualitative nature (44,45), perhaps because of better intestinal absorption of the estolate. Potentially severe but rare cholestatic liver injury occurs in perhaps up to 2-4% of... 

Tolman KG, Sannella JJ, Freston JW. Chemical structure of erythromycin and hepatotoxicity. Ann Intern Med 1974 81(l) 58-60. 

Adverse reactions Erythromycin can cause nausea, vomiting, diarrhea, and abdominal cramping. Gl intolerance due to erythromycin is due to direct stimulation of the motilin receptor, leading to increased Gl motility. This occurs with both the IV and PO formulation. Although rare, all macrolides can cause hepatotoxicity. The estolate formulation of erythromycin has been associated with cholestatic hepatitis in pregnant women. In high doses, all macrolides can cause tinnitus. All macrolides can cause QT prolongation and torsade de points... 

Erythromycin 1.4 h Unknown Abdominal pain idiosyncratic hepatotoxicity with estolate salt. Interaction with fluoroquinolones, cisapride, disopyramide, terfenadine, orasiemizole can induce OT prolongation and torsade de pointes can elevate serum theophylline levels. (Inhibits hepatic cytochrome P-450 3A4.) Administration of more than 4 g/day may cause tinnitus, ototoxicity. 

Combinations of a 2 -ester and a lipophilic acid-addition salt have also been extensively employed. Erythromycin estolate (2 -propionate, lauryl sulphate salt) has been widely used due to its better oral absorption than other forms of erythromycin [62, 67, 68]. Similar results have been found with erythromycin acistrate (2 -acetate, stearate salt) [69, 70], which is reported to be less hepatotoxic in animals than other forms of erythromycin [71], Two salts of 2 -propionylerythromycin,A-acetyIcysteinate (erythromycin stinoprate) and mercaptosuccinate, are being investigated as combinations of an antimicrobial and mucolytic agent [72-74],... 

In erythromycin-11,12-carbonate (11), the cyclic ester locks the structure of the ring predominantly into the 6,9-hemiketal, with only a minor amount of the 9-keto form present [36, 77-79]. As a consequence, the facile dehydration of the 6,9-hemiketal to the 8,9-anhydro derivative (8) is inhibited. The increased stability results in better potency, pharmacokinetics, and tissue penetration than erythromycin [80, 81]. However, concerns about potential hepatotoxicity have prevented its wider usage [71, 82, 83]. 

A study in 9 transplant patients taking ciclosporin found that erythromycin increased the mean trough serum levels of 3 kidney transplant patients sevenfold, from 147 to 1125 nanograms/mL, and of 6 heart transplant patients four- to fivefold, from 185 to 815 nanograms/mL. Acute nephrotoxicity occurred in all 9 patients, and 7 showed mild to severe hepatotoxicity caused by the increased ciclosporin levels. ... 

Erythromycin estolate, which is a complex salt of the propionate of erythromycin (XXIV), and the detergent moiety lauryl sulphate is the only derivative of this antibiotic to produce hepatotoxicity in man [193,194]. An investigational drug erythromycin cetyl sulphate was withdrawn from trials in man when the incidence of hepatotoxic effects reached 10 to 15%. Consequently, Dujovne has examined the role of the detergent anions in these preparations on their toxic actions [193, 194]. 

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