Tetracyclines lipophilicity

Dmg distribution into tissue reservoirs depends on the physicochemical properties of the dmg. Tissue reservoirs include fat, bone, and the principal body organs. Access of dmgs to these reservoirs depends on partition coefficient, charge or degree of ionization at physiological pH, and extent of protein binding. Thus, lipophilic molecules accumulate in fat reservoirs and this accumulation can alter considerably both the duration and the concentration—response curves of dmg action. Some dmgs may accumulate selectively in defined tissues, for example, the tetracycline antibiotics in bone (see Antibiotics,tetracyclines). 

Fig. 3. Conformations of tetracycline (1) (a) lipophilic nonionized form, and (b) polar 2witterionic form (59).

This highly lipophilic tetracycline is the first "one-a-day" tetracycline (when used to treat mild infections). 

Several drug classes, including tetracycline, sulfonamide, and quinolone antibiotics, as well as chlorothiazide, chlorpromazine, and amiodarone hydrochloride, have been shown to be photoantigens. Photosensitivity may persist even after withdrawal of the drug, as has been observed with the antiarrhythmic drug amiodarone hydrochloride, since it is lipophilic and can be stored for extended periods in the body fat (Unkovic et al., 1984). In addition, it is quite common for cross-reactions to occur between structurally related drugs of the same class. 

Differences in clinical effectiveness are partly due to differences in absorption, distribution and excretion of the individual drugs. In general tetracyclines are absorbed irregularly from the gastrointestinal tract and part of the dose remains in the gut and is excreted in the faeces. However this part is able to modify the intestinal flora. Absorption of the more lipophilic tetracyclines, doxycycline and minocycline is higher and can reach 90-100%. The absorption is located in the upper small intestine and is better in the absence of food. Absorption is impaired by chelation with divalent cations. In blood 40-80% of tetracyclines is protein bound. Minocycline reaches very high concentrations in tears and saliva. Tetracyclines are excreted unchanged, in both the urine by passive filtration and in the feces. Tetracyclines are concentrated in the bile via an active... 

By definition, the fraction that enters the circulatory system is eliminated by extrarenal mechanisms (usually metabolism by the liver and other tissues) and is derived by the difference from renal excretion that is, 1 — Fg. The excretory organs are able to eliminate polar compounds such as tetracycline and tylosin more efficiently than compounds that are highly soluble in lipids (i.e., lipophilic) such as metronidazole, erythromycin, clindamycin, and trimethoporin. Thus, the highly lipophilic compounds will not be eliminated until they are metabolized to more polar intermediates. 

Tetracyclines are rapidly but moderately absorbed from the gastrointestinal tract. The degree of oral absorption of the various tetracyclines is also a function of the lipophilicity of the particular compound. The least lipophilic oxytetracycline is the least well absorbed and the most lipophilic doxycycline is the best absorbed, whereas the absorption of the other tetracyclines falls between these two extremes. 

Doxycycline tends to be more active against some bacteria than other tetracyclines. This is probably due to its slower excretion rather than to enhanced oral absorption. Doxycycline is used in cases where cost is unimportant. It is a very lipophilic drug that shows a high bioavailability, being almost completely absorbed after oral administration to different animal species except chickens (250, 251). 

Apart from improving extractions, ion-pairing techniques can also improve liquid-liquid partition cleanup. Examples of effective ion-pairing cleanup procedures have been described in the analysis of tetracycline (60) and penicillin (68) residues in milk using tetrabutylammonium reagent, the resulting ion pairs turned out to be fairly lipophilic and readily extractable with organic solvents. 

Apart from being a diffusional barrier, mucin can also interact with drugs to decrease their bioavailability, as has been shown with tetracycline [106], phenylbutazone, and warfarin [107]. On the other hand, studies in rats showed that binding of some water-soluble drugs to intestinal mucus was essential for their absorption and that damage to the mucus significantly reduced absorption [108], The acidic mucus is essential for lipid absorption and could be important for the diffusion of lipophilic drugs (see below). 

A quantum-corrected fluorescence spectrum of TC HC1 (11 mg/50 ml) in 0.05 N NaOH taken with a Perkin-Elmer spectrofluorometer LS 5 is given in Fig. 12. Various fluorimetric methods of determination of tetracycline antibiotics are reported in literature (116, 117, 118, 119, 120). TC can be dehydrated to ATC by heating in acid solutions and taking the advantage of the greater lipophilicity of ATC it is extracted at about pH 4 - 5 with chloroform and then the fluorescence of aluminium-chelate is measured (116, 121). 

It has been shown that lipophilic solutes permeate very slowly through membranes of Gram-negative bacteria because of the hydrophilic outer leaflet of the bacterial membranes. The dependence of rate of diffusion and the final equilibrium distribution of lipophilic drugs such as fluoroquinolones and tetracyclines which possess multiple protonation sites has been reviewed [103]. 

The method of circular dichroism has been applied in investigations that have determined the reactions between Pt(II) compound and nucleosides, nucleotides, and DNA. Many antimicrobial preparations are excellent ligands. The activity of some of the antimicrobial preparations has been based on their complexing with metal ions. For example, increased effectiveness of tetracycline has been observed after its coordination with Ca. The complex is more lipophilic and very oil-soluble, which explains its transportation through the cell membrane. The opposite situation occurs when the ion-metal is toxic and the coordinated antibiotic serves as carrier through the membrane. 

Doxycycline and minocycline are more lipophilic tetracyclines. They are well absorbed after oral administration. Their half-lives are 16-18 hours. Their higher affinity for fatty tissues improves their effectiveness and changes their adverse effects profile. Local gastrointestinal irritation and disturbance of the intestinal bacterial flora occur less often than with the more hydrophilic drugs, which have to be given in higher oral doses for sufficient absorption. 

Most of the adverse effects of the tetracyclines depend on the concentration of the antibiotic in the affected organ. The more lipophilic drugs are more potent with regard to their bacteriostatic efficacy and hence usually require daily doses below 1 g. 

The lipid solubility of four tetracyclines (minocycline, doxycycline, tetracycline and oxytetracycline) correlates inversely with the mean concentration of antibiotic in plasma and with renal uptake and excretion. Only the more lipophilic minocycline and doxycycline pass across the blood-brain and blood-ocular barriers in detectable concentrations. Table 5.19 gives some of these characteristics of the tetracyclines. These analogues of tetracycline, while active in vitro against meningococci, are... 

Demeclocycline, tetracycline, oxytetracycline, minocycline, and doxycycline are available in the United States for systemic use. Chlortetracycline and oxytetracycline are used in ophthalmic preparations. Methacycline is not available. Other derivatives are available in other countries. The more lipophilic drugs, minocycline and doxycycline, usually are the most active by weight, followed by tetracycline. Resistance of a bacterial strain to any one member of the class may result in cross-resistance to other tetracyclines. Bacterial strains with tetracycline minimum inhibitory concentrations (MICs) of < 4 pg/mL are considered susceptible... 

Lipophilic tetracyclines Doxycycline Minocycline Fluoroquinolones Ketolides Lincosamides Macrolides Phenicols Rifamycins Triamilides... 

As tetracyclines have moderate to high lipophilic properties, the poor bioavailability associated with oral administration is somewhat surprising. Papich and Riviere suggest that causes may be multifactorial. As zwitterions, they are mainly ionized at pHs within GIT liquor. Moreover, feed reduces bioavailability, and tetracyclines chelate with polyvalent cations. Oxytetracycline absorption has been shown, experimentally, to be reduced by feed, dairy products, Ca +, Mg +, Al +, and Fe + ions and antacids. Even though doxycycline has a similar structure, affinity for metals is different from that of oxytetracycline with greater affinity for zinc and less for calcium. 

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