Liver minocycline

Minocycline is associated with a relatively high incidence of hepatotoxicity. In many cases it is quite distinct from minocycline-induced lupus, occurs earlier in the course of treatment (about 1 month), and the mechanism is unknown [62], However, in some cases the liver toxicity merges with the lupus-like syndrome, occurring after about a year of therapy, and is associated with ANA. This form is indistinguishable from idiopathic autoimmune hepatitis [63], and antibodies against Cyp 3A6 and Cyp 2C4 have been reported [64], Diclofenac has also been reported to cause hepatitis with autoimmune features such as ANA [65],... 

Lawrenson, RA. et al., Liver damage associated with minocycline use in acne A systematic review of the published literature and pharmacovigilance data, Drug Safety, 23, 333, 2000. 

Renal function impairment If renal impairment exists, even usual doses may lead to excessive systemic accumulation of the tetracyclines (with the exception of doxycycline and minocycline) and possible liver toxicity. Use lower than usual doses and/or extend the dosing interval. 

Hepatic function impairment Doses more than 2 g/day IV can be extremely dangerous. In the presence of renal dysfunction, and particularly in pregnancy, IV tetracycline more than 2 g/day has been associated with death secondary to liver failure. Hepatotoxicity has been reported with minocycline. Administer with caution reduce the recommended dosage and/or extend the dosing interval. 

Vestibular reactions like dizziness, vertigo, nausea and vomiting are particular for minocycline. Especially in pregnant women and when given in high doses hepatotoxicity has been described. Also patients with preexisting liver disease are susceptible. In patients with kidney disease renal function can further deteriorate. 

The tetracyclines are metabolized in the liver and are concentrated in the bile. Bile concentrations can be up to five times those of the plasma. Doxycycline, minocycline, and chlortetracycline are excreted prima-... 

Minocycline differs from other tetracyclines in that its antibacterial spectrum includes Neisseria meningitidis and it has been used for meningococcal prophylaxis. It is well absorbed from the gut, even after a meal, partly metabolised in the liver and partly excreted in the bile and urine (t/ 15 h). Dose reduction is not necessary when renal function is impaired 200 mg initially is followed by 100 mg 12-hourly. Minocycline but not other tetracyclines may cause a reversible vestibular disturbance with dizziness, tinnitus and impaired balance, especially in women. 

Therapy includes paracentesis -i- thoracocentesis + i.v. albumin solution, pleural drainage or pleurodesis with talc. Recently, pleurodesis using argon beam coagulation + minocycline hydrochloride has been recommended. In the case of refractory hepatic hydrothorax, TIPS or liver transplantation may be indicated. (53)... 

Treatment may be by laparoscopic or surgical fenestration (137,138,140,142-145), injection of alcohol (40%) (146) or minocycline hydrochloride (135, 150), as well as surgical management. (141) Liver transplantation is a rare indication. (147)... 

Minocycline and doxycycline are predominantly eliminated by the liver and biliary tract (70-90%). Therefore, no change in dose is needed in patients with impaired renal function. However, it should be considered that hepatic elimination of doxycychne or minocycline might be accelerated by co-administration of agents that induce hepatic enzymes. 

The authors stated that they did not have any clear information about the absolute and relative risks of hepatitis, whether these were hypersensitivity reactions or autoimmune hepatitis, in patients taking minocycline for varying lengths of time, and that a study of the comparative rates of hepatitis in people exposed to minocycline compared with those not exposed is required. In the meantime, new reports of severe hepatic reactions to minocycline continue to appear (15-17), including one case of autoimmune hepatitis requiring liver transplantation in a woman who had used minocychne 50-200 mg/ day for 3 years (17). Another case of liver transplantation has previously been reported in patients with hepatic failure after minocycline therapy (18). 

Immunoallergic reactions have been reported with minocycline and include lupus-like syndrome, autoimmune hepatitis, eosinophilic pneumonia, hypersensitivity syndrome, a serum sickness-like illness (29), and Sweet s syndrome (SEDA-21, 262) (SEDA-22, 271). Over 60 minocycline-induced cases of lupus-like syndrome and 24 cases of minocycline-induced autoimmune hepatitis were found in a review of the literature (30). In 13 patients, both disorders co-existed. These patients had symmetrical polyarthralgia/polyarthritis, raised liver enzymes, and positive antinuclear antibodies they were also generally antihistone-negative, and only two patients had p-ANCA antibodies. Minocycline-related lupus can also occur in adolescents (31). 

Three adolescents taking therapeutic doses of minocycline for 12-20 months met the 1993 International Autoimmune Hepatitis Group criteria for autoimmune hepatitis. All had hypogammaglobulinemia and positive antinuclear antibody and antismooth muscle antibody titers. Two underwent liver biopsy that showed severe chronic lymphoplasmocytic inflammation, necrosis, and fibrosis. All other causes of liver disease were excluded. One patient had resolution of symptoms after withdrawal of the drug, while two required immunosuppressive therapy. 

Minocycline is almost completely eliminated via the liver and the biliary tract and is therefore safe in patients with pre-existing renal insufficiency. 

Lawrenson RA, Seaman HE, Sundstrom A, Williams TJ, Farmer RD. Liver damage associated with minocycline use... 

The tetracyclines, apart from doxycycline and minocycline, are slowly eliminated by renal excretion (glomerular filtration). Their slow elimination can be attributed to enterohepatic circulation whereby drug excreted by the liver in bile is reabsorbed from the intestine. The half-life of oxytetracycline differs widely between animal species goat (3.4 h), cattle (4.0 h), sheep (5.2 h), dog (6.0 h), pig (6.0 h), donkey (6.5 h), horse (9.6 h), and red-necked wallaby (.Macropus rufogriseus) (11.4 h). Doxycycline, unlike other tetracyclines, is eliminated by biliary excretion and diffusion into the intestine. The half-life of doxycycline is relatively short in dogs (7.0 h) and cats (4.6 h) compared with human beings (16 h). The half-life of doxycycline in chickens (4.8 h) is shorter than in turkeys (10 h) (Santos et al, 1996). Minocycline is mainly eliminated by hepatic metabolism. 

The absorption of tetracyclines from the G1 tract is non-uniform. Up to 30% of chlortetracycline is absorbed. The absorption for tetracycline, oxytetracycline, and demeclo-cycline ranges between 60 and 80%, whereas as much as 90 to 100% of doxycycline and minocycline is absorbed. The absorption of tetracyclines is impaired by divalent cations (calcium, magnesium, and ferrous iron), by aluminum, and by extremely alkaline pHs. Tetracyclines are distributed widely throughout the body fluid, cross the placental barrier, and can accumulate in growing bones. The concentrations of chlortetracycline in spinal fluid are only one fourth of those in plasma. Minocycline, a more lipid-soluble tetracycline, reaches a high concentration in tears and saliva and can eradicate the meningococcal carrier state. The tetracyclines are metabolized in the liver and excreted mainly by the bile and urine. The concentrations of tetracyclines in the bile are ten times higher than those in serum. 

The serum theophylline levels of a 70-year-old woman with normal liver function increased from 9.8 to 15.5 mg/L after she was given minocycline 100 mg twice daily by infusion for 6 days. Her serum theophylline level was 10.9 mg/L 14 days after the minocycline was stopped. ... 

The tetracyclines are a group of antibiotics with the same basic chemical structure they are derivatives of the naphthacene ring system. Compounds of the series differ in the composition of the side chains (Fig. 1). These antibiotics derived from different Streptomyces species show closely related spectra of bacteriostatic properties, with the exception of minocycline, which is very effective against most Staphylococcus strains resistant to other tetracyclines. Absorption, metabolism, and excretion of the different tetracyclines vary, however. After oral application, tetracycline, oxytetracycline, and chlortetracycline are absorbed to a much lesser degree than demethylchlortetracycline, methacycline, or the almost entirely absorbed minocycline. Maximum blood levels are found 2-6 h after oral intake and immediately in the case of intravenous infusion. Half-lives between 8 and 15 h were reported. The tetracyclines diffuse readily across the vascular barrier and are found in various tissues such as the liver, spleen, bone marrow, kidney, skin, and lungs as well as the peritoneal and pericardiac cavities. The tetracyclines are also able to... 

Liver In a review of 261 cases of autoimmune hepatitis, drugs were suspected in 24 cases (9.2%) [81. Nitrofurantoin and minocycline were most commonly impUcated (11 cases each). Comparison with minocychne, nitrofurantoin-induced hepatitis occurred in older patients, who had more inflammatory changes on histology, more radiological imaging abnormalities (73% versus 0%) and were more likely to have jaundice at presentation. Short-term immunosuppression was generally successful and cirrhosis did not develop. 

Liver Autoimmune hepatitis has been reported in a 20-year-old woman who had taken minocycline for 1 year [140 ], in a 17-year-old-woman who had taken minocycline 50 mg/day and an oral contraceptive for about 2 years [141 ], and in three other patients [142 ]. 

A 23-year-old woman was prescribed minocycline for rosacea for 30 days. Four days after discontinuation, she presented with fever and lymphadenopathy. She was presumed to have mononucleosis and was discharged home on clindamycin for facial impetigo after clinical improvement. However, three days later she was readmitted for recurrent fever, severe malaise and acute abdominal pain. She was transferred to the ICU and managed for coagulopathy (INR 4.4) and encephalopathy. Her transaminases were foxmd to be very high (AST 4798 U/L, ALT 2098 U/L) and bilirubin was 12.8 mg/dL. A liver biopsy revealed liver failme, thought to be secondary to minocycline due to exclusion of other potential causes [9 J. 

Kuhn A, Weiler-Normatm C, Schramm C, Kluge S, Behne MJ, Lohse AW, et al. Acute liver feilure following minocycline treatment - a case report and review of the literature. Z Gastroenterol 2012 50 771-5. 

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