| Identification | More | [Name]
Doxycycline | [CAS]
564-25-0 | [Synonyms]
4-(DIMETHYLAMINO)-1,4,4A,5,5A,6,11,12A-OCTAHYDRO-3,5,10,12,12A-PENTAHYDROXY-6-METHYL-1,11-DIOXO-2-NA
4-(DIMETHYLAMINO)-1,4,4 ALPHA,5,5 ALPHA,6,11,12 ALPHA-OCTAHYDRO-3,5,10,12,12 ALPHA-PENTAHYDROXY-6-METHYL-1,11-DIOXO-2-NAPHTHACENECARBOXAMIDE, MONOHYDRATE
4-(DIMETHYLAMINO)-1,4,4ALPHA,5,5ALPHA,6,11,12ALPHA-OCTAHYDRO-3,5,10,12, 12ALPHA-PENTAHYDROXY-6-METHYL-1, 11-DIOXO-2-NAPHTHACENECARBOXAMIDE
(4S,4AR,5S,5AR,6R,12AS)-4-DIMETHYLAMINO-3,5,10,12,12A-PENTAHYDROXY-6-METHYL-1,11-DIOXO-1,4,4A,5,5A,6,11,12A-OCTAHYDRO-NAPHTHACENE-2-CARBOXYLIC ACID AMIDE
DOXYCYCLINE
DOXYCYCLINE HYDRATE
DOXYCYCLINE MONOHYDRATE
,6alpha,12aalpha))-
1,12a-octahydro-3,5-alpha,10,12,12a-alpha-pentahydroxy-6-alpha-methyl-1,11-dio
10,12,12a-pentahydroxy-6-methyl,1,11-dioxo-,(45-(4alpha,4aalpha,5alpha,5aalpha
2-naphthacenecarboxamide,4-alpha-s-(dimethylamino)-1,4,4a-alpha-5,5a-alpha,6,1
4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-4-(dimethylamino)-4
5-hydroxy-alpha-6-deoxytetracycline
5-hydroxy-alpha-6-deoxytetracyclinemonohydrate
6-alpha-deoxy-5-oxytetracycline
6-deoxy-5-hydroxytetracycline
6-deoxy-oxytetracyclin
6-deoxytetracycline
alpha-6-deoxyoxytetracycline
alpha-6-deoxyoxytetracyclinemonohydrate | [EINECS(EC#)]
209-271-1 | [Molecular Formula]
C22H26N2O9 | [MDL Number]
MFCD02682958 | [Molecular Weight]
462.45 | [MOL File]
564-25-0.mol |
| Chemical Properties | Back Directory | [Appearance]
Yellow Solid | [Melting point ]
206-209°C (dec.) | [Boiling point ]
554.44°C (rough estimate) | [density ]
1.3809 (rough estimate) | [refractive index ]
1.6500 (estimate) | [storage temp. ]
Inert atmosphere,2-8°C | [solubility ]
DMSO : 125 mg/mL (281.26 mM; Need ultrasonic) | [pka]
pKa 3.5 (Uncertain);7.7 (Uncertain);9.5 (Uncertain) | [Water Solubility ]
0.63g/L(25 ºC) | [Usage]
Antibacterial | [BCS Class]
3,1 | [InChIKey]
JBIWCJUYHHGXTC-AKNGSSGZSA-N | [SMILES]
C1(=O)[C@]2(O)[C@@]([H])([C@@H](O)[C@@]3([H])C(=C2O)C(=O)C2=C(C=CC=C2O)[C@@H]3C)[C@H](N(C)C)C(O)=C1C(N)=O | [CAS DataBase Reference]
564-25-0(CAS DataBase Reference) | [EPA Substance Registry System]
564-25-0(EPA Substance) |
| Hazard Information | Back Directory | [Chemical Properties]
Yellow Solid | [Originator]
Cyclidox,Protea,Australia | [Uses]
Doxycycline is a semi-synthetic tetracycline prepared by hydrogenolysis of oxytetracycline to remove the 6-hydroxy group. Although the synthesis was reported in 1958, it was not released for use until 1967. Doxycycline, together with minocycline, is regarded as a ‘third generation’ tetracycline largely replacing the analogues and pro-drugs produced in the early 1960s for mainstream antibiotic applications. Like all tetracyclines, doxycycline shows broad spectrum antibacterial and antiprotozoan activity and acts by binding to the 30S and 50S ribosomal subunits, blocking protein synthesis. Doxycycline has been extensively cited in the literature with over 10,000 references. | [Uses]
Doxycycline is used for the same indications as other antibiotics of the tetracycline
series; however, it belongs to the group of long-lasting tetracyclines. In some cases it is
more active with respect to a number of organisms, and is better tolerated than other
tetracyclines. Synonyms of this drug are azudoxat, codidoxal, eftapan, vibramycin, and
others. | [Uses]
tetracycline antibiotics | [Definition]
ChEBI: Tetracycline in which the 5beta-hydrogen is replaced by a hydroxy group, while the 6alpha-hydroxy group is replaced by hydrogen. A semi-synthetic tetracycline antibiotic, it is used to inhibit bacterial protein synthesis a
d treat non-gonococcal urethritis and cervicitis, exacerbations of bronchitis in patients with chronic obstructive pulmonary disease (COPD), and adult periodontitis. | [Indications]
Doxycycline (Vibramycin, Monodox) has similar absorption and durationof-
activity characteristics. Its effectiveness in acne approaches that of minocycline,
when used in the same fashion with similar dosages. Early data suggests
that subantimicrobial doses of doxycycline, 20 mg (Periostat), may play a
therapeutic role in acne by reducing inflammation through anticollagenolytic,
antimatrix-degrading metalloproteinase, and cytokine downregulating properties. | [Manufacturing Process]
Hydrogen was introduced into a standard hydrogenation vessel containing 10
grams 6-deoxy-6-demethyl-6-methylene-5-oxytetracycline hydrochloride(methacycline), 150 ml methanol and 5 grams 5% rhodium on carbon. The
pressure was maintained at 50 psi while agitating at room temperature for 24
hours. The catalyst was then filtered off, the cake washed with methanol and
the combined filtrates were evaporated to dryness. The dry solids were
slurried in ether, filtered and the cake dried. The resulting solids exhibited a
bioactivity of 1,345 units per mg versus K. pneumoniae.
Water (35 ml) was employed to dissolve 8.5 grams of the above product and
the pH was adjusted to 6.0 with triethylamine, sufficient dimethyl formamide
being added to maintain the solids in solution. Cellulose powder (2 kg) was
slurried in water-saturated ethyl acetate and packed into a tower of about 3?
inches diameter, to a height of 3 ft. The product solution was then
chromatographed over this column, developing with about 12 liters watersaturated ethyl acetate. The first product fraction to come from the tower
yielded 1.85 grams 6-epi-6-deoxy-5-oxytetracycline. The next fraction
contained 2.0 grams of 6-deoxy-6-demethyl-6-methylene-5-oxytetracycline.
The third fraction yielded 0.8 grams 6-deoxy-5-oxytetracycline. | [Brand name]
Doxychel (Rachelle); Monodox (Oclassen); Oracea (CollaGenex); Vibramycin (Pfizer). | [Therapeutic Function]
Antibiotic | [Antimicrobial activity]
It
is active against some tetracycline-resistant Staph. aureus and
is more active than other tetracyclines against Str. pyogenes,
enterococci and Nocardia spp. Mor. catarrhalis (MIC 0.5
mg/L), Legionella pneumophila and most strains of Ureaplasma
urealyticum (MIC 0.5 mg/L) are susceptible. | [General Description]
A more recent addition to the tetracycline group of antibioticsavailable for antibacterial therapy is doxycycline,α-6-deoxy-5-oxytetracycline (Vibramycin), first reportedby Stephens et al. in 1958. It was obtained first in smallyields by a chemical transformation of oxytetracycline, butit is now produced by catalytic hydrogenation of methacyclineor by reduction of a benzyl mercaptan derivative ofmethacycline with Raney nickel. The latter processproduces a nearly pure form of the 6α-methyl epimer. The6α-methyl epimer is more than 3 times as active as itsβ-epimer.169 Apparently, the difference in orientation of themethyl groups, which slightly affects the shapes of the molecules,causes a substantial difference in biological effect. Also, absence of the 6-hydroxyl group produces acompound that is very stable in acids and bases and that hasa long biological half-life. In addition, it is absorbed verywell from the GI tract, thus allowing a smaller dose to be administered.High tissue levels are obtained with it, and unlikeother tetracyclines, doxycycline apparently does not accumulatein patients with impaired renal function.Therefore, it is preferred for uremic patients with infectionsoutside the urinary tract. Its low renal clearance may limit itseffectiveness, however, in urinary tract infections.
Doxycycline is available as a hydrate salt, a hydrochloridesalt solvated as the hemiethanolate hemihydrate, and amonohydrate. The hydrate form is sparingly soluble in waterand is used in a capsule; the monohydrate is water insolubleand is used for aqueous suspensions, which are stable for upto 2 weeks when kept in a cool place. | [Pharmaceutical Applications]
6-Deoxy-5β-hydroxytetracycline. A semisynthetic product
supplied as the hyclate, calcium salt or the hydrochloride for
oral and intravenous administration. | [Pharmacokinetics]
Oral absorption： 90%
Cmax 100–200 mg oral： 1.7–5.7 mg/L after 2–3.5 h
100 mg intravenous infusion (1 h)： 2.5 mg/L end infusion
Plasma half-life：18 h
Volume of distribution： 0.9–1.8 L/kg
Plasma protein binding： 90%
Absorption
Doxycycline is rapidly absorbed from the upper gastrointestinal
tract and absorption appears to be linearly related to the
administered dose. Food, especially dairy products, reduces
peak serum concentrations by 20%. Alcohol also delays
absorption. As with other tetracyclines, divalent and trivalent
cations, as in antacids and ferrous sulfate, form chelates
which reduce absorption.
Distribution
The greater lipophilicity of doxycycline is responsible for its
widespread tissue distribution. Concentrations in liver, biliary
system, kidneys and the digestive tract are approximately twice
those in plasma. Within the respiratory tract, it achieves concentrations
of 2.3–6.7 mg/kg in tonsils and 2.3–7.5 mg/kg in maxillary
sinus mucosa. In bronchial secretions concentrations
are about 20% of plasma levels, increasing to 25–35% in the presence
of pleurisy. Gallbladder concentrations are approximately
75% those of plasma, and prostate concentrations are 60–100%.
It penetrates well into the aqueous humor. CSF concentrations
range from 11% to 56% of plasma levels and are not affected by
inflammation. In the elderly, tissue concentrations are 50–100%
higher than in young adults. The half-life remains unaltered and
one explanation is reduced fecal elimination.
Metabolism and excretion
Doxycycline is largely excreted unchanged. Around 35% is
eliminated through the kidneys and the remainder through
the digestive tract. Renal clearance ranges from 1.8 to 2.1 L/h,
and is largely via glomerular filtration, with approximately
70% tubular reabsorption. Alkalinization enhances renal
clearance. Fecal elimination partly reflects biliary excretion
but also includes diffusion across the intestinal wall. Provided
the drug is not chelated, reabsorption occurs with enterohepatic
recycling. The elimination half-life is long (15–25 h).
The half-life and the area under the concentration–time
curve (AUC) are little altered in renal insufficiency, with no
evidence of accumulation after repeat dosing, even in anuric
patients, evidently as a result of increased clearance through
the liver or gastrointestinal tract, since biliary and fecal concentrations
increase in renal failure. Although the plasma elimination
half-life is unchanged, the drug appears to accumulate in
tissues with increasing renal failure, and it has been suggested
that less drug is bound to plasma protein and red cells through
competition with other metabolites, which in turn increases
hepatic elimination. Pharmacokinetics are unaltered by hemodialysis
or peritoneal dialysis. Clearance is decreased by about
half in patients with type IIa and type IV hyperlipidemia.
The plasma elimination half-life is shortened by various
antiepileptic agents including phenytoin, barbiturates and
carbamazepine, presumably as a result of liver enzyme induction,
although there is also evidence for some interference
with the protein binding of doxycycline. | [Clinical Use]
Its once-daily administration and safety in renal insufficiency
make it one of the most widely used tetracyclines. It is used
in the prophylaxis and treatment of malaria in areas in which
resistance to conventional antimalarial agents is common. | [Clinical Use]
Like the other tetracyclines, doxycycline inhibits the pathogen’s protein synthesisby reversibly inhibiting the 30S ribosomal subunit.Bacteria and Plasmodium ribosomal subunits differ significantlyfrom mammalian ribosomes such that this group ofantibiotics do not readily bind to mammalian ribosomesand, therefore, show good selective toxicity. Althoughdoxycycline is a good antibacterial, its use for malaria islimited to prophylaxis against strains of P. falciparumn resistantto chloroquine and sulfadoxine–pyrimethamine.This use normally should not exceed 4 months. Becausethe tetracyclines chelate calcium, they can interfere withdevelopment of the permanent teeth in children. Therefore,their use in children definitely should be short term. Also, tetracycline photosensitivity must be kept in mind, particularlybecause areas where malaria is endemic are also theareas with the greatest sunlight. | [Side effects]
Untoward reactions are generally those typical of the group
but gastrointestinal side effects are less common than with
other tetracyclines due to the lower total dosage and the ability
to administer the drug with meals. Esophageal ulceration
as a result of capsule impaction has been reported. Dental and
bone deposition appear to be less common than with other
tetracycline derivatives. Other adverse phenomena include
occasional vestibular toxicity.
Hypersensitivity reactions include photosensitivity and
eosinophilia, but rarely anaphylaxis. In common with demeclocycline
and chlortetracycline it may be a more powerful
sensitizer than other tetracyclines. It is contraindicated in
patients with acute porphyria because it has been demonstrated
to be porphyrinogenic in animals. | [Synthesis]
Doxycycline, 4-dimethylamino-1,4,4a,5,5a,6,11,12a-oxtahydro-3,5,10,12, 12a-pentahydroxy-6-methyl-1,11-dioxo-2,naphthacencarboxamide (32.3.7), is an isomer of tetracycline that differs only in the placement of one hydroxyl group. Doxycycline can be formally viewed as the result of transferring the C6 hydroxyl group of tetracycline to C5. Doxycycline is synthesized in two different ways from oxytetracycline (32.3.2). One of the ways suggests dehydrating oxytetracycline at C6 by reducing the tertiary hydroxyl group with hydrogen using a rhodium on carbon catalyst.
The second way is analogous to that of giving methacycline, which suggests an oxidation stage of the homoallyl system, except that N-chlorosuccinimide is used as the oxidant, which results in the formation of a naphthacentetrahydrofuran derivative (32.3.8), and which upon being reacted with hydrofluoric acid breaks apart to form an 11a-chloro- 6-exomethylene derivative (32.3.9). Reductive dechlorination of this product using sodium thiosulfate forms the intermediate methacycline (32.3.6), and thiophenol is joined to the methyl group that carry out radical reactions, forming the derivative (32.3.10). This product is reduced by hydrogen over a Raney nickel catalyst, during which reductive desulfurization takes places, giving doxycycline.
| [Drug interactions]
Potentially hazardous interactions with other drugs
Anticoagulants: possibly enhanced anticoagulant
effect of coumarins and phenindione.
Ciclosporin: possibly increases plasma-ciclosporin concentration.
Oestrogens: possibly reduced contraceptive effects of
oestrogens (risk probably small)
Retinoids: possible increased risk of benign
intracranial hypertension - avoid. | [Metabolism]
Doxycycline is well absorbed on oral administration (90–100% when fasting; reduced by
20% by co-consumption with food or milk), has a half-life permitting once-a-day dosing for mild infections,
and is excreted partly in the feces and partly in the urine. | [Dosage forms]
50 mg b.i.d. to q.i.d.; 100 mg q.d. to b.i.d. Recent evidence suggest
that sub-antimicrobial dose of 20 mg b.i.d. is also effective. No dosage
adjustments needed for renal impairment. |
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