3.3.6 Hepatic Effects
3.3.6.A Minocycline Hydrochloride
3.3.6.A.1 Hepatotoxicity
a) Summary
1) There have been reports of minocycline induced LIVER ENZYME ELEVATIONS and HEPATIC FAILURE; however, it is thought that hepatotoxicity due to minocycline is more rare than with tetracycline (Goldstein et al, 2000; Prod Info Dynacin(R), 1996); (Prod Info Minocin(R), 2000a,b,c)(Davies & Kersey, 1989; Min et al, 1992). It has been postulated that liver dysfunction occurs as the result of a hypersensitivity reaction (Min et al, 1992). If hepatic dysfunction occurs minocycline should be discontinued (Gough et al, 1996).
b) The comparison of four cases of minocycline induced AUTOIMMUNE HEPATITIS with 10 cases of sporadic autoimmune hepatitis demonstrated the histologic similarities of the two types of hepatitis making the relevance of recent minocycline ingestion important for appropriate diagnosis (Goldstein et al, 2000). The four subjects with minocycline induced autoimmune hepatitis were seronegative for hepatitis A, B, and C viruses and had positive antinuclear antibody (ANA) titers, none of which were positive for anti-smooth muscle antibody. The mean histologic activity index (HAI) scores in these subjects was 6.7. All four of the minocycline cases were females aged 16 to 52 years-of-age and had been receiving minocycline 100 milligrams per day (mg/d) for the treatment of acne for 4 months to 12 years. Hepatitis resolved with minocycline discontinuation and administration of oral corticosteroids in three cases and azathioprine in one case. None of these subjects' livery biopsy showed microvesicular or macrovesicular steatosis, bile ductile proliferations, intrahepatocyte iron, or periodic acid-Schiff diastase-resistant globules. The ten control cases of hepatitis had not received any hepatitis-causing medications and seven had a positive serum ANA titer with three of these being positive anti-smooth muscle antibody serum titers. The mean HAI score in this group was 5.4.
c) A 20-year-old female experienced minocycline-induced hepatic failure that required liver transplantation after receiving minocycline, 50 to 200 milligrams per day (mg/day) for 3 years as treatment of acne vulgaris (Pohle et al, 2000).
d) In a retrospective review, Gough presented 7 patients with HEPATITIS believed to be caused by minocycline. As of April 1994, 16 patients with hepatitis believed to be caused by minocycline were reported in the United Kingdom. The patients ranged in age from late teens to middle thirties; however, the indication for minocycline use was for the treatment of acne so this age range would be expected. Patients were being treated with minocycline in doses ranging from 50 to 100 milligrams twice daily. The duration of treatment ranged from 6 weeks to 2 years. Signs and symptoms of hepatitis usually resolved upon discontinuation of minocycline. One patient responded well to treatment with corticosteroids. Despite a good response to discontinuation in most patients, 2 patients died of complications of hepatitis (Gough et al, 1996).
e) ACUTE HEPATITIS and exfoliative dermatitis were described in 2 patients receiving minocycline for skin disorders (50 to 100 mg orally twice daily for approximately 1 month). One patient died secondary to hepatic failure, with the other recovering uneventfully (Davies & Kersey, 1989). However, in each case, a definite cause-effect relationship was not established with minocycline. Another case report describes a 17-year-old female who developed exfoliative dermatitis and hepatitis 3 weeks after the initiation of minocycline therapy (MacNeil et al, 1997).
f) After 4 weeks of treatment with minocycline (100 mg BID) for the treatment of acne a patient developed ACUTE HEPATIC FAILURE. The symptoms included rash, fever, malaise, and vomiting for 2 weeks followed by hepatic failure with resulting encephalopathy and coagulopathy, and significant changes in liver function tests. The patient slowly recovered with supportive care (Min et al, 1992).
2) Minocycline, like doxycycline, has a long serum half-life and can be administered at 12 hour intervals. Minocycline interferes with the third stage of bacterial protein synthesis. After amino acids are activated and attached to t-RNA (transfer RNA), the resulting amino acyl-t-RNA migrates to the bacterial ribosome for synthesis of proteins. Minocycline binds to the 30s subunit on the ribosome and inhibits binding of the aminoacyl-t-RNA molecules (Meyers, 1976).
4) In higher concentration, minocycline inhibits mammalian protein synthesis and may aggravate pre-existing renal functional impairment. The drug may interfere with parenteral nutrition in post operative patients by inhibiting utilization of amino acids for protein synthesis (Beard et al, 1969).
