Minocycline
- Product NameMinocycline
- CAS10118-90-8
- MFC23H27N3O7
- MW457.48
- EINECS800-277-5
- MOL File10118-90-8.mol
Chemical Properties
alpha | D25 -166° (c = 0.524) |
Boiling point | 563.31°C (rough estimate) |
Density | 1.3283 (rough estimate) |
refractive index | 1.6500 (estimate) |
solubility | Methanol (Slightly) |
form | Solid |
pka | pKa 2.8 (Uncertain);5.0 (Uncertain);7.8 (Uncertain);9.5 (Uncertain) |
color | Yellow to Dark Orange |
Water Solubility | 52g/L(25 ºC) |
Stability | Light Sensitive |
CAS DataBase Reference | 10118-90-8(CAS DataBase Reference) |
EPA Substance Registry System | Minocycline (10118-90-8) |
Safety Information
Hazardous Substances Data | 10118-90-8(Hazardous Substances Data) |
MSDS
Provider | Language |
---|---|
Minocycline | English |
Usage And Synthesis
Minocycline belongs to the class of medications called tetracycline antibiotics, who has a broader spectrum than the other members of the group. Identified as a long-acting type, it is used to treat infections induced by certain kinds of bacteria. Minocycline is commonly used in the treatment of skin infections, such as inflammatory lesions of non-nodular moderate-to-severe acne vulgaris. It is also used for other skin infections, such as MRSA and Lyme disease. Besides, minocycline is effective to treat urinary tract infections, gallbladder infections, and respiratory tract infections like bronchitis, pneumonia, sinusitis and it is also used for treating Rocky Mountain spotted fever, typhus and other infections caused by the typhus group of bacteria and tick fevers caused by rickettsiae, etc.
Patented in 1961, minocycline was put into commercial use in 1971. It is not a naturally occurring antibiotic, but was synthesized semi-synthetically from natural tetracycline antibiotics by Lederle Laboratories in 1966.
Patented in 1961, minocycline was put into commercial use in 1971. It is not a naturally occurring antibiotic, but was synthesized semi-synthetically from natural tetracycline antibiotics by Lederle Laboratories in 1966.
https://en.wikipedia.org/wiki/Minocycline
http://www.medicinenet.com/minocycline-oral/article.htm
http://bodyandhealth.canada.com/drug/getdrug/ratio-minocycline
http://www.medicinenet.com/minocycline-oral/article.htm
http://bodyandhealth.canada.com/drug/getdrug/ratio-minocycline
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.
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.
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.
ChEBI: A tetracycline analogue having a dimethylamino group at position 7 and lacking the methyl and hydroxy groups at position 5.
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.
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.
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.
Dynacin (Medicis); Minocin (Lederle); Minocin (Triax);
Solodyn (Medicis);Klinomycin;Lederderm;Mino-50;Minomycin.
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.
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.
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.
A semisynthetic tetracycline derivative supplied as the hydrochloride
for oral administration.
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.
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.
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.
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.
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.
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.
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).
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).
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.
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.
Preparation Products And Raw materials
Preparation Products
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