Glioma cell proliferation is only impacted by doxycycline (0.01–10 µg/mL, 4 d) at high concentrations [2]. At concentrations of 1 µg/mL and above, doxycycline (0.01–10 µg/mL, 24 hours) decreases the MT-CO1 protein level in SVG cells [2]. Doxycycline (100 ng/mL, 1 µg/mL; 24 hours) inhibits human cell line growth [4]. Breast cancer cells' ability to proliferate is inhibited by doxycycline (0-250 μM, 72 hours) [5].

In untreated HT mice, doxycycline (oral gavage; 200 or 800 mg/kg; once daily; 3 months) decreases MMP-9 activity in a dose-dependent way [3]. Both tetracycline and doxycycline, once absorbed from the upper gastrointestinal tract, have systemic effects. Doxycycline has a longer half-life than tetracycline and can be taken once or twice daily, which is its primary benefit. While the peak concentrations of the two medications are comparable, doxycycline has a much longer half-life and peaks faster [6].

Cell Viability Assay[2]
Cell Types: LNT-229, G55 and U343 Glioma Cell
Tested Concentrations: 0.01, 0.1, 1 or 10 µg/mL
Incubation Duration: 4 days
Experimental Results: Only affected at high concentrations (10 µg) Glioma cell growth/ml).

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Cell viability assay[2]
Cell Types: SVG Cell
Tested Concentrations: 0.01, 0.1, 1 or 10 µg/mL
Incubation Duration: 24 hrs (hours)
Experimental Results: MT-CO1 protein content diminished at concentrations of 1 µg/mL and higher.

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Cell proliferation assay [4]
Cell Types: MCF 12A, 293T Cell
Tested Concentrations: 100 ng/mL, 1 µg/mL
Incubation Duration: 96 hrs (hours)
Experimental Results: 1 µg/mL resulted in diminished proliferation of MCF 12A and 293T cells.

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Cell viability assay[5]
Cell Types: MCF-7, MDA-MB-468 Cell
Tested Concentrations: 0-250 μM
Incubation Duration: 72 hrs (hours)
Experimental Results: Inhibition of breast cancer cells, MCF-7 and MCF-7 in a dose-dependent manner The IC50 values of MDA-MB-468 were 11.39 μM and 7.13 μM respectively.

Animal/Disease Models: 6-month-old female heterozygous Col3a1-deficient (HT) mice [3]
Doses: 200 or 800 mg/kg
Route of Administration: po (oral gavage); 200 or 800 mg/kg; one time/day; 3-month
Experimental Results: Active MMP-9 is diminished in a dose-dependent manner.

Absorption, Distribution and Excretion
Doxycycline is virtually completely absorbed after oral administration with a bioavailability of ranging from 73-95%. Following an oral dose of 500 mg, the Cmax of 15.3 mg/L was reached in four hours. Following a 200 mg dose, normal adult volunteers averaged peak serum levels of 2.6 mcg/mL of doxycycline at 2 hours, decreasing to 1.45 mcg/mL at 24 hours. While a high-fat meal lowers Cmax and the rate of absorption, the effect is not clinically significant.
Tetracyclines, including doxycycline, are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with a creatinine clearance of about 75 mL/min. This percentage may fall as low as 1-5%/72 hours in individuals with a creatinine clearance below 10 mL/min.
There is limited information available.
Population pharmacokinetic analysis of sparse concentration-time data of doxycycline following standard of care intravenous and oral dosing in 44 pediatric patients two to 18 years of age showed allometrically -scaled clearance (CL) ranging from 3.27 to 3.58 L/h/70 kg.
RELATIVE INSENSITIVITY OF DOXYCYCLINE PHARMACOKINETICS TO RENAL INSUFFICIENCY HAS ... BEEN DEMONSTRATED IN HUMANS & APPEARS TO BE ASSOC WITH INCR FECAL EXCRETION OWING TO DIFFUSION OF DRUG INTO LUMEN OF SMALL INTESTINE. ... RENAL CLEARANCE OF ACTIVE ANTIBIOTIC IS ... 20 ... ML/MIN FOR DOXYCYCLINE ... .
SERUM LEVELS OF DOXYCYCLINE ARE EQUIV WHETHER DRUG IS DOSED BY IV OR PER OS ROUTE. AFTER MULTIPLE DAILY IV DOSES OF 200 MG, SERUM LEVELS ... FLUCTUATED BETWEEN 5-6 & 1-2 UG/ML, WHICH IS ABOVE MIN INHIBITORY CONCN FOR MOST SUSCEPTIBLE PATHOGENS.
URINARY EXCRETION OF ... DOXYCYCLINE IS INCR @ HIGH URINARY PH VALUES. ALKALINE TREATMENT OF SUBJECTS RESULTED IN 24% INCR IN CUMULATIVE URINARY TETRACYCLINE EXCRETION COMPARED WITH ACID TREATMENT (P< 0.05) & 54% INCR FOR DOXYCYCLINE (P LESS THAN 0.05). RENAL CLEARANCE ... INCR DURING ALKALINE TREATMENT ... .
... MORE COMPLETELY ABSORBED AFTER ORAL ADMIN THAN OTHER TETRACYCLINES ... IN PLASMA, IT IS ABOUT 90% PROTEIN BOUND, WHICH IS HIGHEST DEGREE FOR ANY OF TETRACYCLINES.
For more Absorption, Distribution and Excretion (Complete) data for DOXYCYCLINE (20 total), please visit the HSDB record page.

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Metabolism / Metabolites
There is limited information available.
/DOXYCYCLINE/ IS EXCRETED IN FECES (UP TO 90%) AS INACTIVE CONJUGATE OR PERHAPS AS CHELATE.
Although it was previously suggested that doxycycline is partially metabolized in the liver, recent studies indicate that the drug is not metabolized but is partially deactivated in the intestine by chelate formation.

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Biological Half-Life
There is limited information available.
DOXYCYCLINE: ROUTES OF EXCRETION: HEPATIC, RENAL; NORMAL HALF-LIFE: 20 HR; MAINTENANCE DOSE INTERVALS: 12-24 HR.
DOXYCYCLINE IS LONG-ACTING, HAVING SERUM HALF-LIFE OF 15-17 HR AFTER INITIAL DOSE & ABOUT 22 HR AFTER 4TH DAY OF TREATMENT.
The serum half-life of doxycycline is 14-17 hr after a single dose and 22-24 hr after multiple doses in patients with normal renal function. In patients with severe renal impairment, the serum half-life of doxycycline is reported to be 18-26 hr after a single dose, and 20-30 hr after multiple doses. It appears that serum half-life of doxycycline is not altered in patients undergoing hemodialysis. In patients with normal renal function, approximately 20-26% of a single oral or iv dose of doxycycline is excreted in urine and 20-40% is excreted in feces within 48 hr as active drug. In patients with creatinine clearances less than 10 ml/minute, the fraction of doxycycline excreted in urine within 72 hr may decrease to about 1-5%.

Hepatotoxicity
Doxycycline has been associated with rare instances of hepatic injury, generally arising within 1 to 2 weeks of starting therapy, sometimes with a history of previous administration of the agent without injury. The pattern of injury ranges from hepatocellular to cholestatic and is probably most commonly mixed. The onset is often abrupt and can be accompanied by signs of hypersensitivity, such as fever, rash and eosinophilia (DRESS syndrome). Recovery is usually rapid and usually complete within 4 to 6 weeks. However, instances of severe and prolonged cholestatic liver injury have been reported with oral doxycycline. The autoimmune-like hepatitis that has been described with minocycline has not been linked to doxycycline, despite similarities in chemical structure and similar indications and uses, perhaps because it is used less frequency in a low dose, long term regimen. High dose intravenous doxycycline can cause acute fatty liver typical of that caused by intravenous tetracycline, particularly in susceptible patients such as pregnant women. This type of injury is, however, quite rare. Nevertheless, for these reasons, the duration and dose of parenteral doxycycline therapy should be minimized.
Likelihood score: B (highly likely but rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
A number of reviews have stated that tetracyclines are contraindicated during breastfeeding because of possible staining of infants’ dental enamel or bone deposition of tetracyclines. However, a close examination of available literature indicates that there is not likely to be harm in short-term use of doxycycline during lactation because milk levels are low and absorption by the infant is inhibited by the calcium in breastmilk. Doxycycline use in children <8 years is now considered acceptable in courses up to 21 days. As a theoretical precaution, avoid prolonged (>21 days) or repeat courses during nursing. Monitor the infant for rash and for possible effects on the gastrointestinal flora, such as diarrhea or candidiasis (thrush, diaper rash).
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
While there is limited information available, tetracyclines bound to plasma proteins in varying degree.

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Interactions
ORAL ADMIN OF FERROUS SULFATE (200-600 MG) INTERFERES WITH ABSORPTION OF ... /DOXYCYCLINE/ FROM GI TRACT & VICE VERSA, LEADING TO DECR SERUM LEVELS OF ANTIBIOTIC & IRON SALT, RESPECTIVELY. IF SIMULTANEOUS ADMIN IS NECESSARY, PATIENTS SHOULD RECEIVE ... /DOXYCYCLINE/ 3 HR AFTER OR 2 HR BEFORE IRON ADMIN.
DOXYCYCLINE HAS BEEN REPORTED TO INTERACT WITH ALUMINUM HYDROXIDE.
The half-life of doxycycline may be decr by concurrent administration of carbamazepine (Tegretol), phenytoin (Dilantin), or barbiturates, which incr the hepatic metabolism of this antibiotic.
CONCOMITANT USE OF TETRACYCLINES & CORTICOSTEROIDS MAY RESULT IN SUPERINFECTION. ... INCREASED BLOOD UREA NITROGEN LEVELS /IN PATIENTS RECEIVING TETRACYCLINES & DIURETICS/. ... TETRACYCLINES SHOULD NOT BE ADMIN CONCOMITANTLY WITH OTHER POTENTIALLY HEPATOTOXIC DRUGS. /TETRACYCLINES/
For more Interactions (Complete) data for DOXYCYCLINE (11 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 MOUSE ORAL 1007.45 MG/KG
LD50 MOUSE IV 204-222.5 MG/KG

[1]. A combinatorial strategy for treating KRAS-mutant lung cancer. Nature. 2016 Jun 30;534(7609):647-51.

[2]. Doxycycline Impairs Mitochondrial Function and Protects Human Glioma Cells from Hypoxia-Induced Cell Death: Implications of Using Tet-Inducible Systems. Int J Mol Sci. 2018 May 17;19(5):1504.

[3]. Doxycycline ameliorates the susceptibility to aortic lesions in a mouse model for the vascular type of Ehlers-Danlos syndrome. J Pharmacol Exp Ther. 2011 Jun;337(3):621-7.

[4]. Doxycycline alters metabolism and proliferation of human cell lines. PLoS One. 2013 May 31;8(5):e64561.

[5]. Doxycycline inhibits the cancer stem cell phenotype and epithelial-to-mesenchymal transition in breast cancer. Cell Cycle. 2017 Apr 18;16(8):737-745.

[6]. Tight Long-term dynamic doxycycline responsive nigrostriatal GDNF using a single rAAV vector. Mol Ther. 2009 Nov;17(11):1857-67.

[7]. Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10933-8.

[8]. Niv Y. Doxycycline in Eradication Therapy of Helicobacter pylori--a Systematic Review and Meta-Analysis. Digestion. 2016;93(2):167-73.

Therapeutic Uses
Antibiotics, Tetracycline
AGAINST GRAM-POSITIVE BACTERIA IT IS ABOUT TWICE AS POTENT AS TETRACYCLINE, EXCEPT THAT IT IS UP TO 10 TIMES AS POTENT AGAINST STREP VIRIDANS. FURTHERMORE, STRAINS OF STREP FAECALIS THAT ARE RESISTANT TO OTHER TETRACYCLINES MAY BE SENSITIVE TO DOXYCYCLINE.
DOSE OF DOXYCYCLINE FOR ADULTS IS 100 MG EVERY 12 HR DURING FIRST 24 HR, FOLLOWED BY 100 MG ONCE DAY, OR TWICE DAILY WHEN SEVERE INFECTION IS PRESENT. CHILDREN OVER 8 YR SHOULD RECEIVE 4-5 MG/KG/DAY, DIVIDED INTO 2 EQUAL DOSES GIVEN @ 12 HR INTERVAL DURING FIRST DAY, AFTER WHICH SINGLE DOSE OF HALF THIS AMT IS ADMIN.
AFFINITY OF DOXYCYCLINE FOR METALLIC IONS MAY NOT BE AS GREAT AS THAT OF OTHER TETRACYCLINES SINCE IT CAN BE GIVEN WITH FOOD OR MILK WITHOUT SIGNIFICANT INACTIVATION OR IMPAIRMENT OF ABSORPTION.
For more Therapeutic Uses (Complete) data for DOXYCYCLINE (27 total), please visit the HSDB record page.

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Drug Warnings
TETRACYCLINES SHOULD NOT BE ADMIN TO PREGNANT OR NURSING WOMEN & CHILDREN UNDER 8 YR UNLESS THERE ARE COMPELLING REASONS TO DO SO.
TREATMENT OF PREGNANT PATIENTS ... MAY PRODUCE DISCOLORATION OF TEETH IN THEIR OFFSPRING. ... CHILDREN UP TO 8 YR OLD MAY BE SUSCEPTIBLE ... TETRACYCLINES ARE DEPOSITED IN SKELETON DURING GESTATION. ... 40% DEPRESSION OF BONE GROWTH ... DEMONSTRATED IN PREMATURE INFANTS TREATED WITH THESE AGENTS. /TETRACYCLINES/
TETRACYCLINES POSE SPECIAL DANGER IN PREGNANT WOMEN, WITH RESPECT TO POSSIBLE HEPATIC INJURY, PARTICULARLY IF USED FOR TREATMENT OF PYELONEPHRITIS, RELATIVELY COMMON OCCURRENCE IN SUCH PATIENTS INDEED, FATALITIES HAVE OCCURRED. /TETRACYCLINES/
IT SHOULD BE EMPHASIZED THAT CROSS-SENSITIZATION AMONG VARIOUS TETRACYCLINES IS COMMON.
For more Drug Warnings (Complete) data for DOXYCYCLINE (12 total), please visit the HSDB record page.

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Pharmacodynamics
Doxycycline and other tetracyclines are mainly bacteriostatic and are thought to exert antimicrobial effects by the inhibition of protein synthesis. They suppress the growth of bacteria or keep them in the stationary phase of growth. Tetracyclines have antimicrobial spectrum of activity against a variety of gram-positive and gram-negative microorganisms. Cross-resistance of these microorganisms to tetracyclines is a common occurrence. As it is a highly lipophilic drug, doxycycline crosses multiple membranes of target molecules. Doxycycline shows favorable intra-cellular penetration, with bacteriostatic activity against a wide range of bacteria. Doxycycline also exhibits antiparasitic properties and anti-inflammatory actions. Its anti-inflammatory effects were investigated in various inflammatory skin conditions, such as bullous dermatoses and rosacea.

C22H24N2O8

444.44

444.153

564-25-0

Doxycycline hydrochloride;10592-13-9;Doxycycline hyclate;24390-14-5;Doxycycline calcium;94088-85-4

54671203

Light yellow to brown solid powder

1.6±0.1 g/cm3

685.2±55.0 °C at 760 mmHg

206-209ºC

368.2±31.5 °C

0.0±2.2 mmHg at 25°C

1.737

1.36

6

9

2

32

956

6

C[C@@H]1[C@H]2[C@@H]([C@H]3[C@@H](C(=O)C(=C([C@]3(C(=O)C2=C(C4=C1C=CC=C4O)O)O)O)C(=O)N)N(C)C)O

JBIWCJUYHHGXTC-AKNGSSGZSA-N

InChI=1S/C22H24N2O8/c1-7-8-5-4-6-9(25)11(8)16(26)12-10(7)17(27)14-15(24(2)3)18(28)13(21(23)31)20(30)22(14,32)19(12)29/h4-7,10,14-15,17,25,27-29,32H,1-3H3,(H2,23,31)/t7-,10+,14+,15-,17-,22-/m0/s1

2-Naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-, (4S,4aR,5S,5aR,6R,12aS)-

Doxycycline BMY 28689 BU 3839T BU-3839TBMY28689BMY-28689Azudoxat

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~125 mg/mL (~281.26 mM)
H2O : < 0.1 mg/mL

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.68 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.68 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)