Home
Up

Chlortetracycline

Chlortetracycline (Aureomycin,) is the first tetracycline to be identified;  it was discovered in 1945 as the product of an actinomycete cultured from a soil sample collected from Sanborn Field at the University of Missouri [1]. The organism was named Streptomyces aureofaciens and the isolated drug, Aureomycin, because of their golden color.

Therapeutic use

The main use of chlortetracycle is in veterinary indications.

Dosage and Administration

 

Toxicology

 

Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
dog LD50 intravenous 150mg/kg (150mg/kg)   "Handbook of Toxicology," 4 vols., Philadelphia, W.B. Saunders Co., 1956-59Vol. 5, Pg. 52, 1959.
dog LD50 oral 750mg/kg (750mg/kg)   Antimicrobial Agents Annual. Vol. -, Pg. 595, 1960.
guinea pig LDLo intraperitoneal 1800mg/kg (1800mg/kg)   Antibiotiki. Vol. 20, Pg. 793, 1975.
mouse LD50 intracrebral 48mg/kg (48mg/kg) BEHAVIORAL: EXCITEMENT

BEHAVIORAL: "HALLUCINATIONS, DISTORTED PERCEPTIONS"

MUSCULOSKELETAL: CHANGES IN TEETH AND SUPPORTING STRUCTURES
Chemotherapy Vol. 26, Pg. 196, 1980.
Link to PubMed
mouse LD50 intravenous 134mg/kg (134mg/kg)   Antibiotics and Chemotherapy Vol. 6, Pg. 623, 1956.
mouse LD50 oral 1500mg/kg (1500mg/kg)   Antimicrobial Agents Annual. Vol. -, Pg. 595, 1960.
mouse LDLo intraperitoneal 192mg/kg (192mg/kg)   Compilation of LD50 Values of New Drugs.
mouse LDLo subcutaneous 3gm/kg (3000mg/kg)   Antibiotics and Chemotherapy Vol. 6, Pg. 623, 1956.
rat LD50 intravenous 118mg/kg (118mg/kg)   Antibiotics and Chemotherapy Vol. 6, Pg. 623, 1956.
rat LDLo intraperitoneal 335mg/kg (335mg/kg)   Compilation of LD50 Values of New Drugs.
rat LDLo oral 3gm/kg (3000mg/kg)   Journal of Agricultural and Food Chemistry. Vol. 17, Pg. 497, 1969.

 

Pharmacokinetic

Bioavailability 30%
Protein binding 50 to 55%
Metabolism Hepatic (75%)
Half-life 5.6 to 9 hours
Cmax (mg/ml) 1.4
tmax (hrs) 3
Distribution volume Vd (l) 100
Excretion Renal and biliary (>50%)

Absorption

Oral doses of chlortetracycline ranging from 6 to 800 mg/kg bw were administered to female white rats and to guinea pigs [2]. In general, there was no direct proportional correlation of serum chlortetracycline concentration with dose. Administration of the same dose daily for nine days gave higher serum levels than those found with the single doses.

Rats given single oral doses of 75 mglkg bw of chlortetracycline attained plasma levels averaging 2.1 mg/l one hour post dosing. Plasma concentrations declined to 0.8 mg/l by six hours after dosing [3].

Beagle dogs given single oral chlortetracycline doses of 25 mg/kg bw showed peak serum levels ranging from 0.40 to 1.9 mg/l two hours after dosing which declined to an average of 0.21 mg/l after 24 h [4]. When the dogs were given a single IV dose of 10 mg/kg chlortetracycline, serum levels averaged 6.6 mg/l at one hour post dosing; declining to 2.4 mg/l at 8 h, 0.29 mg/l at 24 h and 0.06 mg/l at 48 h.

Adult white rabbits were given single oral doses of two different formulations of chlortetracycline at 20 mg/kg by stomach tube [5]. Serum levels of chlortetracycline averaged 2.3 mg/l three hours after dosing; declining to 0.82 mg/l after 12 h and 0.09 mg/l after 24 h.

Distribution

In a study of the intestinal absorption in rats, tissue levels of chlortetracycline at 1 to 5 hours after dosing are shown in Table 1. Tissue levels were highest in liver and kidney at all times [3]. In a study in which adult white rabbits were given single oral doses of two different formulations of chlortetracycline by stomach tube at 20 mg/kg, levels of the drug twenty-four hours after dosing were highest in liver, averaging 1.84 mg/kg, followed by kidney, lung and heart. No measurable chlortetracycline was found in muscle tissue in this experiment [5]. Studies in rats [6], mice and rabbits [7] have shown that chlortetracycline has a great affinity for bones and teeth, and remains in these tissues and structures for long periods of time.

Table 1. Chlortetracycline Levels in Tissues and Plasma of Rats Following a Single Oral Dose of 75 mg/kg bw [3].

Time After Dosing, min

Chlortetracycline (mg/kg)

Plasma Lungs Brain Liver Kidney
60 2.1 0.56 5.20.13 0.11 0.04 16.20.6 21.86.4
120 1.1 0.2 3.82.1 0.090.03 21.40.9 20.14.9
180 0.80.4 2.3 1.0 0.020.01 15.2 1.2 14.83.2
240 0.70.6 2.20.9 0.030.02 10.00.7 11.21.0
360 0.80.3 2.1 0.45 0.030.01 5.3 1.0 8.70.66

14C-labeled chlortetracycline was administered IV to two beagle dogs to study the distribution throughout the body. Four hours after dosing the liver contained most radioactivity, followed in decreasing order by the kidney, ileum, jejunum, heart and duodenum. A large proportion of the recovered radioactivity was found in the urine, intestinal contents and bile. With the exception of subcutaneous fat, radioactivity was found throughout all tissues and fluids examined [8](Kelly. A summary of the findings is presented in Table 2.

Table 2. Total Micrograms of Chlortetracycline in the Whole Tissues of Dogs Four Hours After an Intravenous Dose of 10 mg/kg [8]

Tissue Dog A Dog B Tissue Dog A Dog B
Liver 5638 7782 Jejunum 559 723
Kidney  805 718 Ileum 755 790
Heart 634 529 Cecum 168 40
Lungs 366 426  Colon 255 156
Brain 69 60 Rectum 101 154
Bile 2750 3240 Stomach Contents 39 31
Spleen 123 102 Duodenal Contents 146 238
Pancreas 173 164 Jejunal Contents 845 876
Uterus 50 80 Ileal Contents 2146 2128
Trachea 36 44 Colon Contents 2481 1293
Esophagus 70 92 Rectal Contents 21 749
Stomach 230 347 Diaphragm 150 181
Duodenum 538 540 Urine 20711 N.M.

Dog A Body Weight 6.2 kg and Dog B 8.0 kg; NM = Not Measured

Excretion

 

Metabolism

Quantitative studies in which 14C-labeled chlortetracycline hydrochloride was administered by oral, intraperitoneal (lP) and intravenous (IV) routes to adult male Wistar rats and by the IV route to male beagle dogs have been reported [9,10]. Orally administered chlortetracycline was excreted primarily in the faeces, whereas after IP dosing the amounts recovered from feces and urine were approximately the same. Urinary excretion predominated after IV administration of chlortetracycline at 15 mg/kg but as the dose was raised, the ratio of urinary to fecal excretion shifted to favor fecal excretion at an IV dose of 60 mg/kg. The major 'metabolite', was identified as 4-epichlortetracycline, which accounted for 23 to 35 % of the radioactivity recovered in the urine in rat studies and 32 to 60% in the dog study. This epimer is essentially inactive in the microbiological assay.

The extent to which epimerisation occurs in vivo, if at all, is not clear, since this epimerisation is known to occur readily chemically and it is possible that epimerisation occurred under the conditions used for extraction of fecal samples. In an in vitro experiment, approximately 20% of 14C-labeled chlortetracycline added to normal dog urine was recovered as the 4-epichlortetracycline after 24 hours.

Mechanism of Action

Protein synthesis inhibitor. All tetracyclines act by the inhibiting attachment of aminoacyl-t RNA to the A site on the 30S ribosome to prevent protein synthesis. Translation is inhibited by 1 molecule of the tetracycline per ribosome. It is postulated that a tetracycline-magnesium complex is formed at the ribosome, making it less flexible and therefore unable to bind aminoacyl-t RNA. It has been found that binding of tetracyclines to the 30S ribosome is dependent on proteins S7, S14 and S19 [11].

Other pharmacological effects

Chlortetracycline is a specific and potent calcium ionophore antibiotic. The compound has been shown to inhibit binding of aminoacyl-tRNA to ribosomes. In endoplasmic reticulum studies Chortetracycline has been used as a fluorescent dye to analyze calcium changes during apotosis, and in other processes. Chlortetracycline has been shown to block platelet secretion and can affect 17beta-estradiol (E2) synthesis in H295R cells. Kupffer cell studies have shown that Chlortetracycline can inhibit secretion of TNF alpha.


Medicinal Chemistry

CAS number: 57-62-5   EINECS: 200-341-7
 

Molecular Formula: C22H23ClN2O8

Average mass: 478.879608 Da

Monoisotopic mass: 478.114288 Da

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

SMILES: C1[C@@H]2[C@@](C(=C3C(c4c(ccc(c4[C@@]([C@@H]13)(C)O)Cl)O)=O)O)(C(C(C(N)=O)=C([C@H]2N(C)C)O)=O)O

Std. InChI:1S/C22H23ClN2O8/c1-21(32)7-6-8-15(25(2)3)17(28)13(20(24)31)19(30)22(8,33)18(29)11(7)16(27)12-10(26)5-4-9(23)14(12)21/h4-5,7-8,15,26,28-29,32-33H,6H2,1-3H3,(H2,24,31)/t7?,8-,15-,21-,22-/m0/s1
 

ACD/LogP: 1.323 # of Rule of 5 Violations: 2
ACD/LogD (pH 5.5): -1.21 ACD/LogD (pH 7.4): -1.64
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: 7
#Freely Rotating Bonds: 7 Polar Surface Area: 181.62 Å2
Index of Refraction: 1.745 Molar Refractivity: 113.915 cm3
Molar Volume: 281.089 cm3 Polarizability: 45.159 10-24cm3
Surface Tension: 101.96199798584 dyne/cm Density: 1.704 g/cm3
Flash Point: 450.372 C Enthalpy of Vaporization: 125.108 kJ/mol
Boiling Point: 821.078 C at 760 mmHg Vapour Pressure: 0 mmHg at 25C

Major Impurities: Epichlortetracycline (8 % max.)

Appearance: Yellow powder

Melting point: 168-169 C

Optical rotation: [a]D23 = -275 (MeOH)

Solubility: Water = 8.6 g/l, MeOH = 17.4 g/l, EtOH = 1.7 g/l

Stability: Chlortetracycline hydrochloride and the calcium salt of chlortetracycline are stable 2 and 3 years, respectively, at room temperature.

Manufacture: Chlortetracycline is an antibacterial agent obtained by aerobic fermentation of a strain of Streptomyces aureofaciens. It is obtained commercially by large scale fermentation.





 

 


1. Jukes, Thomas H. Some historical notes on chlortetracycline. Reviews of Infectious Diseases 1985, 7(5): 702-707.

2. Eisner, H.J., Stern, K.E., Dornbush, A.C. and Oleson, J.J. J Pharmacol Exp Ther, 1953, 442-449.

3. Berte, F. and Vandoni, G. Chemotherapia, S, 1962, 219-230.

4. Kanegis, L. Antibiotic A-VIII. The comparative pharmacology ofthe tetracyclines, American Cyanamid Company Report P.R. 1958, 4, 884-921.

5. Neuschl, J. Arch Exp Veterinarmed, 1991, 45,105-112.

6. Buyske, D.A., Eisner H.J. and Kelly, R.G. J Pharm Exper Therapy, 1960, 130, 150-156.

7. Miller, B.L. and Wyatt, R.D. Poultry Sci, 1985, 64, 1637-1643.

8. Kelly, R.G. American Cyanamid Company Report P.R. 1964, 9, 485-492. (Pearl River).

9. Wulf, R.J. and Eisner, H.J. American Cyanamid Company Report C.P. 1961, 1, 626-683. (Pearl River).

10. Eisner, H.J. and Wulf, R.J. J. Pharmacol. Exp. Ther, 1963, 142, 122-131.

11. Sande, M.A., and Mandell, G.L. Antimicrobial Agents. Tetracyclines, Chloramphenicol, Erythromycine and Miscellaneous Antibacterial Agents in Goodman and Gillmans' The Pharmacological Basis of Therapeutics, 8th Edition, Gilman, A.G., Rail, T.W., Nies, A.S. and Taylor. P. (eds), 1990, p 1117-1145.

 

     Hit Counter

 

Send mail to stefano.biondi@innovativesolution.it with questions or comments about this web site.
Copyright 2010 Innovative Solution di Biondi Stefano