Minocycline

Absorption

100mg of oral minocycline reaches a Cmax of 1.6mg/L, with a Tmax of 1.9h, and an AUC of 31.6mg/L*h. 200mg of oral minocycline reaches a Cmax of 3.1mg/L, with a Tmax of 2.5h, and an AUC of 48.3mg/L*h.

Toxicity

The oral LD50 in rats is 2380mg/kg and in mice is 3600mg/kg. The intraperitoneal LD50 in rats is 331mg/kg and in mice is 299mg/kg. The subcutaneous LD50 in rats is 1700mg/kg and in mice is 2290mg/kg.
Patients experiencing an overdose may present with dizziness, nausea, and vomiting. In the event of an overdose, discontinue minocycline and treat patients with symptomatic and supportive measures.

Description

An important antibiotic produced by semisynthesis from demeclocycline is minocycline. It is much more lipophilic than its precursors, gives excellent blood levels following oral administration (90–100% available),and can be given once a day. Its absorption is lowered by approximately 20% when taken with food or milk. It is less dependent on active uptake mechanisms and has a somewhat broader antimicrobial spectrum. It also, apparently, is less painful on IM or IV injection, but it has vestibular toxicities (e.g., vertigo, ataxia, and nausea) not generally shared by other tetracyclines.

Originator

Minocin,Lederle ,US,1971

The Uses of Minocycline

Minocycline is a semi-synthetic tetracycline prepared by sequential hydrogenolysis, nitration and reductive methylation. Minocycline, together with doxycycline, is regarded as a ‘third generation’ tetracycline largely replacing the natural products and pro-drugs produced in the early 1950s for mainstream antibiotic applications. Like all tetracyclines, minocycline shows broad spectrum antibacterial and antiprotozoan activity and acts by binding to the 30S and 50S ribosomal sub-units, blocking protein synthesis. Minocycline has been extensively cited in the literature with over 5,000 references.

The Uses of Minocycline

Minocycline is used for the same indications as other antibiotics of the tetracycline series. In a few cases, it is tolerated worse than other tetracyclines, and in particular, it has an effect on the vestibular apparatus. In addition, as seen already from the synthesis scheme, it is much more expensive than other tetracyclines, which are synthesized in a purely microbiological manner. Synonyms of this drug are clinocin, minocyn, vectrin, and others.

Background

Minocycline was first described in the literacture in 1966. It is a second generation tetracycline antibiotic that is active against gram-negative and gram-positive bacteria. Like other semisynthetic tetracyclines, minocycline has modifications to carbons 7-9 on the D ring to generate higher efficacy than previous tetracyclines.
Minocycline was granted FDA approval on 30 June 1971.

Indications

Oral and topical minocycline are indicated to treat inflammatory lesions of acne vulgaris. Subgingival microspheres are indicated as an adjunct treatment in the reduction of pocket depth in adults with periodontitis. Oral and intravenous formulations are indicated to treat infections of susceptible microorganisms. These include rickettsiae, Mycoplasma pneumoniae, Chlamydia trachomatis, Chlamydophila psittaci, Chlamydia trachomatis, Ureaplasma urealyticum, Borrelia recurrentis, Haemophilus ducreyi, Yersinia pestis, Francisella tularensis, Vibrio cholerae, Campylobacter fetus, Brucella species, Bartonella bacilliformis, Klebsiella granulomatis, Escherichia coli, Enterobacter aerogenes, Shigella species, Acinetobacter species, Haemophilus influenzae, and Kelbsiella species.

Definition

ChEBI: A tetracycline analogue having a dimethylamino group at position 7 and lacking the methyl and hydroxy groups at position 5.

Indications

The tetracycline antibiotic minocycline (Minocin) is modestly effective in the treatment of rheumatoid arthritis and is generally well tolerated. Radiographic evidence of its efficacy as a DMARD is lacking, although clinical symptoms do abate. It can be useful in the treatment of early, mild disease.

Manufacturing Process

Preparation of 7-(N,N'-Dicarbobenzyloxyhydrazino)-6-Demethyltetracycline: A1.0 g portion of 6-demethyltetracycline was dissolved in a mixture of 9.6 ml oftetrahydrofuran and 10.4 ml of methanesulfonic acid at -10°C. The mixturewas allowed to warm to 0°C. A solution of 0.86 g of dibenzyl azodicarboxylatein 0.5 ml of tetrahydrofuran was added dropwise and the mixture was stirredfor 2 hours while the temperature was maintained at 0°C. The reactionmixture was added to ether. The product was filtered off, washed with etherand then dried. The 7-(N,N'-dicarbobenzyloxyhydrazino)-6-demethyltetracycline was identified by paper chromatography.
Reductive Methylation of 7-(N,N'-Dicarbobenzyloxyhydrazino)-6-Demethyl-6-Deoxytetracycline to 7-Dimethylamino-6-Demethyl-6-Deoxytetracycline: Asolution of 100 mg of 7(N,N'-dicarbobenzyloxyhydrazino)-6-demethyl-6-deoxytetracycline in 2.6 ml of methanol, 0.4 ml of 40% aqueous ormaldehyde solution and 50 mg of 5% palladium on carbon catalyst washydrogenated at room temperature and two atmospheres pressure. Uptake ofthe hydrogen was complete in 3 hours. The catalyst was filtered off and thesolution was taken to dryness under reduced pressure. The residue wastriturated with ether and then identified as 7-dimethylamino-6-demethyl-6-deoxytetracycline by comparison with an authentic sample, according to USPatent 3,483,251.

brand name

Dynacin (Medicis); Minocin (Lederle); Minocin (Triax); Solodyn (Medicis);Klinomycin;Lederderm;Mino-50;Minomycin.

Therapeutic Function

Antibiotic

World Health Organization (WHO)

Minocycline, a semi-synthetic tetracycline derivative was introduced in 1967. It is used today in the treatment of bacterial, rickettsial and amoebic infections. Symptoms described as dizziness or vertigo have been recognized in association with minocycline administration, however, these symptoms are usually not severe. Minocycline is registered in many countries and the World Health Organization is not aware that registration has been refused elsewhere.

Antimicrobial activity

It exhibits the broad-spectrum activity typical of the group, but retains activity against some strains of Staph. aureus resistant to older tetracyclines. It is active against β-hemolytic streptococci and some tetracycline- resistant pneumococci. It is also active against some enterobacteria resistant to other tetracyclines, probably because some Gram-negative efflux pumps remove minocycline less effectively than other tetracyclines. Some strains of H. influenzae resistant to other tetracyclines are susceptible. Sten. maltophilia is susceptible, as are most strains of Acinetobacter spp. and L. pneumophila.
It is notable for its activity against Bacteroides and Fusobacterium spp., and is more active than other tetracyclines against C. trachomatis, brucellae and nocardiae. It inhibits Mycobacterium tuberculosis, M. bovis, M. kansasii and M. intracellulare at 5–6 mg/L. Candida albicans and C. tropicalis are also slightly susceptible.

Pharmaceutical Applications

A semisynthetic tetracycline derivative supplied as the hydrochloride for oral administration.

Pharmacokinetics

Minocycline is a tetracycline antibiotic that binds to the bacterial 30S ribosomal subunit and interferes with protein synthesis. It is generally given 2-4 times daily, so the duration of action is short. Intravenous minocycline should not exceed 400mg in 24 hours. Patients should be counselled regarding the risks related to tooth and bone development, pseudomembranous colitis, central nervous system side effects, and pseudotumor cerebri.

Pharmacokinetics

Oral absorption： 95–100%
Cmax 150 mg oral： 4 mg/L after 2h
300 mg oral： 2 mg/L after 2 h
Plasma half-life： 12–24 h
Volume of distribution： 80–115 L
Plasma protein binding： 76%
Absorption
Food does not significantly affect absorption, which is depressed by co-administration with milk. It is chelated by metals and suffers the effects of antacids and ferrous sulfate common to tetracyclines. On a regimen of 100 mg every 12 h, steady-state concentrations ranged between 2.3 and 3.5 mg/L.
Distribution
The high lipophilicity of minocycline provides wide distribution and tissue concentrations that often exceed those of the plasma. The tissue:plasma ratio in maxillary sinus and tonsillar tissue is 1.6： that in lung is 3–4. Sputum concentrations may reach 37–60% of simultaneous plasma levels. In bile, liver and gallbladder the ratios are 38, 12 and 6.5, respectively.
Prostatic and seminal fluid concentrations range from 40% to 100% of those of serum. CSF penetration is poor, especially in the non-inflamed state. Concentrations in tears and saliva are high, and may explain its beneficial effect in the treatment of meningococcal carriage.
Metabolism
Biotransformation to three microbiologically inactive metabolites occurs in the liver： the most abundant is 9-hydroxyminocycline.
Excretion
Only 4–9% of administered drug is excreted in the urine, and in renal failure elimination is little affected. Neither hemodialysis nor peritoneal dialysis affects drug elimination. Fecal excretion is relatively low and evidence for enterohepatic recirculation remains uncertain. Despite high hepatic excretion, dose accumulation does not occur in liver disease, such as cirrhosis. Type IIa and type IV hyperlipidemic patients show a decreased minocycline clearance of 50%, suggesting that dose modification may be necessary.

Clinical Use

There appear to be few situations in which it has a unique therapeutic advantage over other tetracyclines. Its use has been tempered by the high incidence of vestibular side effects.
Although used in the long-term management of acne, the potential for skin pigmentation must be considered. Because of its high tissue concentrations, it may occasionally provide a useful alternative to other agents for the treatment of chronic prostatitis. It has a role in the treatment of sexually transmitted chlamydial infections.

Side Effects

Minocycline shares the untoward reactions common to the group with gastrointestinal side effects being most common, and more prevalent in women. Diarrhea is relatively uncommon, presumably as a result of its lower fecal concentrations. Hypersensitivity reactions, including rashes, interstitial nephritis and pulmonary eosinophilia, are occasionally seen.
Staining of the permanent dentition occurs with all tetracyclines; a side effect that appears to be unique to minocycline is that of tissue discoloration and skin pigmentation. Tissues that may become pigmented include the skin, skull and other bones and the thyroid gland, which at autopsy appears blackened. The pigmentation tends to resolve slowly with discontinuation of the drug and is related to the length of therapy.
Three types of pigmentation have been identified:
? A brown macular discoloration (‘muddy skin syndrome’), which occurs in sun-exposed parts and is histologically associated with melanin deposition.
? Blue–black macular pigmentation occurring within inflamed areas and scars associated with hemosiderin deposition.
? Circumscribed macular blue–gray pigmented areas occurring in sun-exposed and unexposed skin, which appears to be linked to a breakdown product of minocycline.
CNS toxicity has been prominent, notably benign intracranial hypertension, which resolves on discontinuation of the drug, and, more commonly, dizziness, ataxia, vertigo, tinnitus, nausea and vomiting, which appear to be more frequent in women. These primarily vestibular side effects have ranged in frequency from 4.5% to 86%. They partly coincide with plasma concentration peaks, but their exact pathogenesis has yet to be determined.

Synthesis

Minocycline, 4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12 a-octahydro- 3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacencarboxamide (32.3.17), is synthesized from 6-dimethyl-tetracycline (32.3.11), which is synthesized as a result of the vital activity of S. aureofaciens, in which the mechanism of transferring methyl groups is disrupted, or from a common strain of the same microorganisms, but with the addition of compounds such as ethionin, D-norleucine or D-methionine to the medium for developing this actinomycete, which are antimetabolytes of methionine, the primary donor of methyl groups in microbiological synthesis of tetracycline molecules. Hydrogenolysis of the aforementioned 6-demethyltetracycline (32.3.11) with hydrogen using a palladium on carbon catalyst gives 4-dimethylamino-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo- 2-napthacencarboxamide (32.3.12), which is nitrated at position 9 by potassium nitrate in aqueous hydrofluoric acid, which forms the nitro compound (32.3.13). This is reduced to the corresponding amino derivative (32.3.14) by hydrogen over platinum dioxide. The resulting aminophenyl compound (32.3.14) is then nitrated with nitric acid in the presence of sulfuric acid to make 7-nitro-9-amino-4-naphthacencarboxamide (32.3.15).
This undergoes diazotization when reacted with butylnitrate in sulfuric acid, and the resulting diazo derivative (32.3.16) is reduced with hydrogen using a palladium on carbon catalyst. During this, the product is deazotized, while the nitro group is simultaneously reduced to an amino group, which undergoes exhaustive methylation by formaldehyde into minocycline (32.3.17).

Drug interactions

Potentially hazardous interactions with other drugs
Anticoagulants: possibly enhanced anticoagulant effect of coumarins and phenindione.
Oestrogens: possibly reduced contraceptive effect of oestrogens (risk probably small)
. Retinoids: possibly increased risk of benign intracranial hypertension - avoid.

Metabolism

Minocycline is primarily metabolized to 9-hydroxyminocycline. It is also metabolized to 2 different N-demethylated metabolites.

Metabolism

Undergoes some metabolism in the liver, mainly to 9-hydroxyminocycline.

Dosage forms

Up to 200 mg daily in divided doses.