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Chlortetracycline
Clomocycline
Demeclocycline
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Lymecycline
Meclocycline
Methacycline
Minocycline
Oxytetracycline
Penimepicycline
Pipacycline
Rolitetracycline
Tetracycline

Tetracyclines

 The first tetracycline, chlortetracycline (Fig. 1), was described in 1948 as a product isolated from Streptomyces aureofaciens. Oxytetracycline and tetracyline itself (so-called because it lacks both the chlorine of chlortetracycline and the hydroxyl of oxytetracycline) quickly followed. This class of antibiotics include: Doxycycline, Chlortetracycline, Clomocycline, Demeclocycline, Lymecycline, Meclocycline, Metacycline, Minocycline, Oxytetracycline, Penimepicycline, Rolitetracycline, Tetracycline.

All can be administered orally except for rolitetracycline.

Figure 1. chemical structure of chlortetracycline

Tetracyclines have a broad spectrum, displaying good activity against most Gram-positive and Gram-negative bacteria (excluding Proteus spp. and Pseudomonas aeruginosa), rickettsiae, chlamydiae, mycoplasmas, and spirochaetes. They share similar antibacterial activity but are distinguished by their pharmacokinetic profile. Doxycycline and minocycline are the most widely used and are almost completely absorbed when given orally. They do not aggravate renal failure so that can be used in renally impaired patients; they also exhibit marginally better antibacterial activity and sufficiently long serum half-lives to allow them to be given only once or twice daily.

Susceptible bacteria concentrate tetracyclines by active transport. In the cell they interfere with the binding of aminoacyl tRNA to the A site on the ribosome. Like chloramphenicol, the tetracyclines are predominantly bacteriostatic. The mechanism of the most common form of resistance is mediated by the production of a new protein which prevents uptake of the drug. There is almost complete cross-resistance between tetracyclines, although minocycline may retain activity against some tetracycline-resistant strains.

Classification of Tetracyclines

Historically, tetracyclines are considered First generation if they are obtained by biosynthesis such as: Tetracycline, Chlortetecycline, Oxytetracycline, Demeclocycline. Second generation if they are derivatives of semi-synthesis such as: Doxycycline, Lymecycline, Meclocycline, Methacycline, Minocycline, Rolitetracycline. Third generation if they are obtained from total synthesis such as: Tigecycline. However, some researchers consider Tigecycline to be distinct from other tetracyclines  drugs and are considered as a new family of antibacterials called Glycylcyclines.

Figure 2. Structures of tetracyclines and their pharmacological action.

Therapeutic use

The therapeutic use of tetracyclines has declined over the years with the increase of resistance, particularly among enterobacteria and streptococci. They are still widely used for the treatment of respiratory infections, particularly chronic bronchitis and mycoplasma pneumonia. They are the drugs of choice for rickettsial and chlamydial infections of all types but newer macrolides may take their place.

Tetracyclines are active against malaria parasites and some other protozoa. Doxycycline is sometimes used for antimalarial prophylaxis and in combination with quinine in the treatment of Plasmodium falciparum infections.

Pharmacokinetics

The pharmacokinetic profile of tetracyclines has recently been reviewed  [1].

Table 1. Pharmacokinetics of tetracyclines.
Agent Formulations Percentage absorption Doses (mg) Peak concentration (Cmax) (mg/ml) Time to peak concentration (tmax) (hrs) Half life (t1/2) (hrs) Protein binding (%) Volume of distribution (l/kg or l) Elimination
urinary faecal
tetracycline po/iv 77-88 250

300

500

2

2.5

3-5

2-4

3

2

6-11

7.8

8.5

55-64

 

 

1.3l/kg or 108l

 

30

 

 

20-60

 

 

oxytetracycline po/iv 58 250

500

2

4

3

 

9.2

 

27-35

 

128l

 

- 50
chlortetracycline po 25-30 500 1.4 3 5.6 50-55 100l - 50
demeclocycline po 66 150

300

500

1.2

1.7

2.5

4

4

6

-

10-17

13

75-91

 

 

1.7l/kg or 121l 40

 

 

43

 

 

Lymecycline po - 300 2.1 3 8 - - 25 -
methacycline po 58 300 2-3 3 14 75-78 - 33 -
rolitetracycline iv - 275

300

2-4

4-6

-

 

5-8

 

-

 

-

 

>50

 

-

 

Absorption

For most agents absorption is in the range 25–60%. Serum concentrations rise slowly after oral administration with absorption occurring in the stomach, duodenum and small intestine. Cmax (mg/ml) depends on dose, but is generally in the range 1–5 mg/ml. tmax is in the range 2–4 hrs except for demeclocycline whose Cmax is delayed until 4–6 hrs. Tetracyclines form insoluble complexes with divalent and trivalent cations like calcium, magnesium, iron and aluminium, which markedly reduces absorption [2]. Protein, fat and carbohydrate meals reduce the absorption of tetracycline by about 50% [3].

Distribution

The volume of distribution (Vd) of tetracyclines is in the order of 1.3–1.7 l/kg or a total volume of distribution of 100–130 l. Protein binding is variable.

Excretion

Unchanged tetracyclines are excreted by renal and bilary routes. Renal elimination (ClR) is related to glomerular filtration for most agents, with the exception of chlortetracycline [4-5]. With the exception of rolitetracycline, the amount of drug excreted in the urine is <50%. More than 40% is found in the faeces after biliary elimination and for most drugs enterohepatic circulation [6]. Biliary concentrations can exceed blood by a factor of 5 [7].

Metabolism

None of these agents undergoes metabolism with the exception of tetracycline, 5% of which is excreted as the metabolite D-epitetracycline.

 

 


1. Kenneth N. Agwuh and Alasdair MacGowan, Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines Journal of Antimicrobial Chemotherapy 2006, 58, 256–265.

2. Neuvonen PJ. Interactions with the absorption of tetracyclines. Drugs 1976, 11, 45–54.

3. Welling PG, Koch PA, Lav CC et al. Bioavailability of tetracycline and doxycycline in fasted and non-fasted subjects. Antimicrob Agents Chemother 1977, 11, 462–9.

4. Klein NC, Cunha BA. Tetracyclines. Med Clin North Am 1995, 79, 789–801.

5. Kunin CM, Rees SB, Merrill JP et al. Persistence of antibiotics in blood of patients with acute renal failure I tetracycline and chlortetracycline. J Clin Invest 1959, 38, 1487–97.

6. Fabre J, Milek E, Kalpopoulos et al. La Cinetique des tetracyclines chez I’homme. Schweiz med Wschr 1977, 101, 573–8.

7. Vincon G, Albin J, Paccalin J et al. Elimination des antibiotiques dans la bile. Bordeaux Medical 1979, 12, 795–9.
 

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