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Minocycline

Minocycline is a semisynthetic tetracycline developed by Lederle in 1972, and marketed under the brand name Minocin [1].

Minocycline is a broad-spectrum tetracycline antibiotic, and has a broader spectrum than the other members of the group. It is a bacteriostatic antibiotic, classified as a long-acting type. As a result of its long half-life it generally has serum levels 2–4 times that of the simple water-soluble tetracyclines.

Minocycline is the most lipid-soluble of the tetracycline-class antibiotics, giving it the greatest penetration into the prostate and brain, but also the greatest amount of central nervous system (CNS)-related side effects, such as vertigo.

Therapeutic use

Minocycline and doxycycline are frequently used for the treatment of acne vulgaris.[2] Both of these closely related antibiotics have similar levels of efficacy, although doxycycline has a slightly lower risk of adverse side effects.[3] Historically, minocycline has been a very effective treatment for acne vulgaris [4]. However, acne that is caused by antibiotic resistant bacteria is a growing problem in many countries [5]. The therapeutic use of minocycline includes the treatment of infections caused by susceptible strains of microorganisms, such as Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsial pox and tick fevers caused by Rickettsiae, upper respiratory tract infections caused by Streptococcus pneumoniae and for the treatment of asymptomatic carriers of Neisseria meningitidis.

Minocycline is also used for other skin infections such as MRSA [6] as well as Lyme disease [7], using a dosing regimen of twice daily 100 mg. Its activity against Lyme disease is enhanced by its superior ability to cross the blood-brain barrier. It may be used to treat  drug resistant acinetobacter infections [8].

Both minocycline and doxycycline have shown effectiveness in asthma due to immune suppressing effects.[9] Minocycline as well as doxycycline have modest effectiveness in treating rheumatoid arthritis.[10] It is recognized as a Disease-Modifying Anti-Rheumatic Drug by the American College of Rheumatology, which recommends its use as a treatment for rheumatoid arthritis.

Dosage and Administration

 

Toxicology

Minocycline has been observed to cause a dark discoloration of the thyroid in experimental animals (rats, minipigs, dogs and monkeys). In the rat, chronic treatment with minocycline has resulted in goiter accompanied by elevated radioactive iodine uptake and evidence of thyroid tumor production. Minocycline has also been found to produce thyroid hyperplasia in rats and dogs.

LD50=2380 mg/kg (rat, oral), LD50=3600 mg/kg (mouse, oral).

Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
infant TDLo oral 12mg/kg/2D-I (12mg/kg) BRAIN AND COVERINGS: INCREASED INTRACRANIAL PRESSURE

GASTROINTESTINAL: NAUSEA OR VOMITING
Therapie. Vol. 38, Pg. 93, 1983.
 
man TDLo oral 343mg/kg/17W- (343mg/kg) BLOOD: EOSINOPHILIA

LIVER: LIVER FUNCTION TESTS IMPAIRED

LIVER: "HEPATITIS (HEPATOCELLULAR NECROSIS), DIFFUSE"
American Journal of Gastroenterology. Vol. 91, Pg. 1641, 1996.
mouse LD50 intracrebral 38mg/kg (38mg/kg) BEHAVIORAL: "HALLUCINATIONS, DISTORTED PERCEPTIONS"

BEHAVIORAL: EXCITEMENT

MUSCULOSKELETAL: CHANGES IN TEETH AND SUPPORTING STRUCTURES
Chemotherapy Vol. 26, Pg. 196, 1980.
mouse LD50 intraperitoneal 310mg/kg (310mg/kg)   "Antibiotics: Origin, Nature, and Properties," Korzyoski, T., et al., eds., Washington, DC, American Soc. for Microbiology, 1978Vol. 1, Pg. 501, 1978.
mouse LD50 intravenous 140mg/kg (140mg/kg)   "Antibiotics: Origin, Nature, and Properties," Korzyoski, T., et al., eds., Washington, DC, American Soc. for Microbiology, 1978Vol. 1, Pg. 501, 1978.
mouse LD50 oral 3100mg/kg (3100mg/kg)   "Antibiotics: Origin, Nature, and Properties," Korzyoski, T., et al., eds., Washington, DC, American Soc. for Microbiology, 1978Vol. 1, Pg. 501, 1978.
women TDLo oral 8mg/kg (8mg/kg)   American Journal of Medicine. Vol. 109, Pg. 340, 2000.
women TDLo oral 8mg/kg (8mg/kg) SKIN AND APPENDAGES (SKIN): "DERMATITIS, ALLERGIC: AFTER SYSTEMIC EXPOSURE" American Journal of Medicine. Vol. 109, Pg. 340, 2000.
women TDLo oral 28mg/kg/2W-I (28mg/kg) SENSE ORGANS AND SPECIAL SENSES: VISUAL FIELD CHANGES: EYE

BRAIN AND COVERINGS: "CHANGES IN CIRCULATION (HEMORRHAGE, THROMBOSIS, ETC.)"

BEHAVIORAL: HEADACHE
Annals of Internal Medicine. Vol. 127, Pg. 168, 1997.
women TDLo oral 100mg/kg (100mg/kg) KIDNEY, URETER, AND BLADDER: HEMATURIA

KIDNEY, URETER, AND BLADDER: INTERSTITIAL NEPHRITIS

KIDNEY, URETER, AND BLADDER: PROTEINURIS
British Medical Journal. Vol. 1, Pg. 524, 1979.
women TDLo oral 112mg/kg/4W-I (112mg/kg)   American Journal of Gastroenterology. Vol. 91, Pg. 1641, 1996.
women TDLo oral 112mg/kg/4W-I (112mg/kg) LIVER: LIVER FUNCTION TESTS IMPAIRED

SKIN AND APPENDAGES (SKIN): "DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE"
American Journal of Gastroenterology. Vol. 91, Pg. 1641, 1996.
women TDLo oral 730mg/kg/1Y-I (730mg/kg) GASTROINTESTINAL: NAUSEA OR VOMITING

BEHAVIORAL: ANOREXIA (HUMAN

LIVER: LIVER FUNCTION TESTS IMPAIRED
American Journal of Gastroenterology. Vol. 91, Pg. 1641, 1996.
women TDLo oral 1204mg/kg/86W (1204mg/kg) MUSCULOSKELETAL: JOINTS British Journal of Rheumatology. Vol. 33, Pg. 674, 1994.
women TDLo oral 17520mg/kg/12 (17520mg/kg) SKIN AND APPENDAGES (SKIN): "DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE"

SENSE ORGANS AND SPECIAL SENSES: OTHER: EYE

MUSCULOSKELETAL: CHANGES IN TEETH AND SUPPORTING STRUCTURES
American Journal of Ophthalmology. Vol. 125, Pg. 396, 1998.
 

 

Uncommon side effects (with prolonged therapy) include skin discolouration and autoimmune disorders that are not seen with other drugs in the class. Minocycline can cause the rare condition of secondary intracranial hypertension which has initial symptoms of headache, visual disturbances, dizziness, vomiting, and confusion. Cerebral edema, as well as autoimmune rheumatoid arthritis are rare side effects to minocycline in some people [11].

Adverse Reactions

Minocycline may cause upset stomach, diarrhea, dizziness, unsteadiness, drowsiness, mouth sores, headache and vomiting. Minocycline increases sensitivity to sunlight. It has also been linked to cases of lupus. Minocycline can reduce the effectiveness of oral contraceptives. Prolonged use of minocycline over an extended period of time can lead to blue-gray skin and blue-gray staining of scar tissue is not permanent but it can take a very long time for the skin colour to return to normal; on the other hand a muddy brown skin colour in sun exposed areas is usually a permanent skin discolouration.[12] Permanent blue discoloration of gums or teeth discoloration may also occur. Rare but serious side effects include fever, yellowing of the eyes or skin, stomach pain, sore throat, vision changes, and mental changes, including depersonalization [13].

Occasionally minocycline therapy may result in autoimmune disorders such as drug related lupus and auto-immune hepatitis. Significant or complete recovery occurs in most people who develop minocycline induced autoimmune problems within a period of a couple of weeks to a year of cessation of minocycline therapy. Autoimmune problems emerge during chronic therapy but can sometimes occur after only short courses of a couple of weeks of therapy [14-15]. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome can occur during the first few weeks of therapy with minocycline [15].

Minocycline, but not other tetracyclines, can cause vestibular disturbances with dizziness, ataxia, vertigo and tinnitus. These effects are thought to be related to minocycline's greater penetration into the central nervous system. Vestibular side effects are much more common in women than in men, occurring in 50% to 70% of women receiving minocycline. As a result of the frequency of this bothersome side effect, minocycline is rarely used in female patients [16].

Symptoms of an allergic reaction include rash, itching, swelling, severe dizziness, and trouble breathing. Minocycline has also been reported to very rarely cause idiopathic intracranial hypertension (pseudotumor cerebri) [17], a side effect also more common in female patients.

Thyroid cancer has been reported in the post-marketing setting in association with minocycline products. When minocycline therapy is given over prolonged periods, monitoring for signs of thyroid cancer should be considered.

Pharmacokinetic

There are no data on the effects of age, sex, changes in body mass, co-morbidity or infection on the pharmacokinetics of minocycline except for a small number of studies carried out in patients with renal impairment and end stage renal disease. Renal impairment and end stage renal disease have little effect on the serum concentrations and serum half-life or AUC of minocycline [24, 25, 30, 31] in both single dose and short multi-dosing studies.

Table 1. Pharmacokinetic of minocycline

Dose and route Single (SD) or multiple dose (MD) Cmax (mg/ml) Tmax (hrs) T1/2 (hrs) AUC (mg.h/l)
50mg po SD 0.65 - - 2.1 (0-6hrs)
200mg po SD 3.1 2 17 43.9 (0-24hrs)
200 mg po SD tablet 3.5 2-4 12.9 47.6 (0-24hrs)
200 mg po SD capsule 3.6 2-4 13.1 46.7 (0-24hrs)
200 mg iv SD 3.0 - 17 85.8 (0-8hrs)
200mg iv MD 4.1 - 21 69.8 (0-8hrs)

 

Bioavailability 100%
Metabolism hepatic
Cmax  
Vd (l) 80-115
Half-life 11-22 hrs
Eliminiation rate Constant  
Excretion mainly fecal, rest renal
Protein binding 55-76%

Absorption

Minocycline is almost completely absorbed (95–100%) [18], mainly in the stomach, duodenum and jejunum. Unlike other tetracyclines, food does not appear to have an effect on either the Cmax or AUC [19]. The Cmax increases dose proportionally: 0.65 mg/L after 50 mg, 2.2 mg/L after 150 mg, and 3–3.6 mg/L after a 200 mg dose [19-22]. Absorption is reduced by iron and antacids containing calcium and magnesium [23].

Distribution

There is little data on the volume of distribution of  minocycline, values of 80–115 L have been reported [24] or 1.17 L/kg [25]. As with other tetracyclines, there is very little good quality data on tissue penetration. However, a tissue/serum concentration ratio of >10 has been reported for liver and bile; 5–10 for duodenum, gall bladder and thyroid; and <2 for colon, bladder, prostate, uterus, breast, skin, lymph nodes and veins [26]. No minocycline has been detected in saliva and concentrations of <50% serum in CSF have been reported [27].

Elimination

The amount of minocycline recovered in the urine is about 5–12% of the dose. Faecal elimination accounts for about 20–35% of the dose [21, 24, 26, 28]. Renal clearance is about 2.2–1.2 mL/min [25].

Metabolism

Up to six metabolites of minocycline have been described, some of which have antibacterial activity and are found in urine. The principal metabolite is 9-hydroxyminocycline; the other two main metabolites are mono-N-demethylated derivatives. Epimerization of minocycline also results in the formation of 4-epiminocycline[29].

Mechanism of action

Minocycline passes directly through the lipid bilayer or passively diffuses through porin channels in the bacterial membrane. Tetracyclines like minocycline bind to the 30S ribosomal subunit, preventing the binding of tRNA to the mRNA-ribosome complex and interfering with protein synthesis.

Microbiology

Minocycline produced a –1.5 ± 1.0 log kill against S. aureus, –2.0 ± 0.8 log kill against E. coli and +0.3 ± 1.8 log growth with K. pneumoniae. MBCs (mg/ml) are 2-fold higher than the MIC for S. pneumoniae and 2–4 times the MIC for S. aureus.

Using a hollow fibre in vitro model to simulate free drug serum concentrations of oral minocycline 200 mg/day in man, the 24 hrs antibacterial effect was a –1.8 ± 0.2 log reduction in count by 24 h against MRSA [32].


Medicinal Chemistry

CAS number: 10118-90-8   EINECS:

Molecular Formula: C23H27N3O7

Average mass: 457.47641 Da

Monoisotopic mass:  457.184906 Da

Systematic name: (4S,4aS,5aR,12aS)-4,7-Bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-tetracenecarboxamide

SMILES: [C@@H]12[C@](C(=C3[C@H](C2)Cc2c(C3=O)c(ccc2N(C)C)O)O)(C(=O)C(=C([C@H]1N(C)C)O)C(=O)N)O

Std. InChI: 1S/C23H27N3O7/c1-25(2)12-5-6-13(27)15-10(12)7-9-8-11-17(26(3)4)19(29)16(22(24)32)21(31)23(11,33)20(30)14(9)18(15)28/h5-6,9,11,17,27,29-30,33H,7-8H2,1-4H3,(H2,24,32)/t9-,11-,17-,23-/m0/s1

ACD/LogP: -0.652 # of Rule of 5 Violations: 2
ACD/LogD (pH 5.5): -3.28 ACD/LogD (pH 7.4): -3.43
ACD/BCF (pH 5.5): 1.00 ACD/BCF (pH 7.4): 1.00
ACD/KOC (pH 5.5): 1.00 ACD/KOC (pH 7.4): 1.00
#H bond acceptors: 10 #H bond donors: 6
#Freely Rotating Bonds: 7 Polar Surface Area: 164.63 Å2
Index of Refraction: 1.717 Molar Refractivity: 116.049 cm3
Molar Volume: 294.562 cm3 Polarizability: 46.006 10-24cm3
Surface Tension: 90.0429992675781 dyne/cm Density: 1.553 g/cm3
Flash Point: 439.603 °C Enthalpy of Vaporization: 122.471 kJ/mol
Boiling Point: 803.272 °C at 760 mmHg Vapour Pressure: 0 mmHg at 25°C

logP = 0.05
 


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