Alodox - Pharmacology Doxycyline Hyclate

The structural formula of doxycycline hyclate is:

with a molecular formula of (C₂₂H₂₄N₂O_8.HCI)_2.C₂H₆O.H₂Oand a molecular weight of 1025.89. The chemical designation fordoxycycline is 4-(dimethylamino)-1, 4, 4a, 5, 5a, 6, 11,12a-octahydro-3, 5, 10, 12, 12a-pentahydroxy-6 -methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride, compound withethyl alcohol (2:1), monohydrate.

Doxycycline hyclate is a yellow to light-yellow crystalline powder which is soluble in water.

Eachtablet for oral administration contains 23mg doxycycline hyclateequivalent to 20 mg of doxycycline. In addition, each tablet containsthe following inactive ingredients: anhydrous lactose, carnauba wax,croscarmellose sodium, hypromellose, magnesum stearate,microcrystalline cellulose, poldextrose, polyethylene glycol, titaniumdioxide, and triacetin.

After oral administration, doxycycline hyclate israpidly and nearly completely absorbed from the gastrointestinaltract. Doxycycline is eliminated with a half-life of approximately 18hours by renal and fecal excretion of unchanged drug.

Doxycycline has been shown to inhibit collagenase activity in vitro. ¹Additional studies have shown that doxycycline reduces the elevatedcollagenase activity in the gingival crevicular fluid of patients withadult periodontitis.²³ The clinical significance of these findings is not known.

Doxycycline is a member of the tetracycline class of antibiotics. Thedosage of doxycycline achieved with this product during administrationis well below the concentration required to inhibit microorganismscommonly associated with adult periodontitis. Clinical studies withthis product demonstrated no effect on total anaerobic and facultativebacteria in plaque samples from patients administered this dose regimenfor 9 to 18 months. This product should not be used for reducing thenumbers of or eliminating those microorganisms associated withperiodontitis.

The pharmacokinetics of doxycline following oraladministration of doxycycline hyclate were investigated in 4 volunteerstudies involving 107 adults. Additionally, doxycyclinepharmacokinetics have been characterized in numerous scientificpublications^4.

In long term therapy, periodic laboratory evaluations of organ
systems, including hematopoietic, renal, and hepatic studies should be performed.

Doxycycline hyclate was assessed for potential to induce carcinogenesis in a study in which the compound
was administered to Sprague-Dawley rats by gavage at dosages of 20, 75, and 200
mg/kg/day for two years. An increased incidence of uterine polyps was observed in
female rats that received 200 mg/kg/day, a dosage that resulted in a systemic
exposure to doxycycline approximately nine times that observed in female humans
that used doxycycline hyclate (exposure comparison based upon AUC values). No
impact upon tumor incidence was observed in male rats at 200 mg/kg/day, or in
either gender at the other dosages studied. Evidence of oncogenic activity was
obtained in studies with related compounds, i.e., oxytetracycline (adrenal and
pituitary tumors), and minocycline (thyroid tumors).

Doxycycline hyclate demonstrated no potential to cause genetic toxicity in an in
vitro point mutation study with mammalian cells (CHO/HGPRT forward mutation
assay) or in an in vivo micronucleus assay conducted in CD-1 mice. However, data
from an in vitro assay with CHO cells for potential to cause chromosomal aberrations
suggest that doxycycline hyclate is a weak clastogen.

Oral administration of doxycycline hyclate to male and female Sprague-Dawley rats
adversely affected fertility and reproductive performance, as evidenced by increased
time for mating to occur, reduced sperm motility, velocity, and concentration,
abnormal sperm morphology, and increased pre-and post-implantation losses.
Doxycycline hyclate induced reproductive toxicity at all dosages that were examined
in this study, as even the lowest dosage tested (50 mg/kg/day) induced a statistically
significant reduction in sperm velocity. Note that 50 mg/kg/day is approximately 10
times the amount of doxycycline hyclate contained in the recommended daily dose
of doxycycline hyclate for a 60 kg human when compared on the basis of body
surface area estimates (mg/m2). Although doxycycline impairs the fertility of rats
when administered at sufficient dosage, the effect of doxycycline hyclate on human
fertility is unknown.

1. Golub L.M., Sorsa T., Lee H-M, Ciancio S., Sorbi D., Ramamurthy N.S., Gruber
B., Salo T.,Konttinen Y.T.: Doxycycline inhibits Neutrophil (PMN)-type Matrix
Metalloproteinases in Human Adult Periodontitis Gingiva. J. Clin. Periodontol
1995; 22: 100-109.
2. Golub L.M., Ciancio S., Ramamurthy N.S., Leung M., McNamara T.F.: Low-dose
Doxycycline Therapy: Effect on Gingival and Crevicular Fluid Collagenase
Activity in Humans. J. Periodont Res 1990; 25: 321-330.
3. Golub L.M., Lee H.M., Greenwald R.A., Ryan M.E., Salo T., Giannobile W.V.: A
Matrix Metalloproteinase Inhibitor Reduces Bone-type Collagen Degradation
Fragments and Specific Collegenases in Gingival Crevicular Fluid During Adult
Periodontitis. Inflammation Research 1997; 46: 310-319.
4. Saivain S., Houin G.: Clinical Pharmacokinetics of Doxycycline and Minocycline.
Clin. Pharmacokinetics 1988; 15: 355-366.
5. Schach von Wittenau M., Twomey T.: The Disposition of Doxycycline by Man
and Dog. Chemotherapy 1971; 16: 217-228.
6. Campistron G., Coulais Y., Caillard C., Mosser J., Pontagnier H., Houin G.:
Pharmacokinetics and Bioavailability of Doxycycline in Humans. Arzneimittel
Forschung 1986; 36: 1705-1707.