Doxycycline, lipid solubility

Doxycycline (6-deoxy-5-hydroxytetracycline, Vibramycin, III) is, chemically, the most stable tetracycline in current use but its outstanding property is its high lipid solubility these features combine to make it the most reliably and completely absorbed tetracycline derivative, with the longest half-life. 

The tetracyclines are distributed throughout body tissues and fluids in concentrations that reflect the lipid solubility of each individual agent. Minocycline and doxycycline are the most lipid soluble, while oxytetracy-chne is the least hpid soluble. The tetracyclines penetrate (but somewhat unpredictably) the uninflamed meninges and cross the placental barrier. Peak serum levels are reached approximately 2 hours after oral administration cerebrospinal fluid (CSF) levels are only one-fourth those of plasma. 

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... 

The tetracyclines are distributed into most tissues, except the CNS (therapeutic levels may be achieved when the meninges are inflamed). Doxycycline is the most lipid-soluble tetracycline... 

Rapid i.v. administration of tetracyclines can result in hypotension and collapse. This has been attributed to intravascular chelation of calcium and/or a decrease in blood pressure owing to the drug vehicle. The i.v. administration of doxycycline to horses causes tachycardia, systemic arterial hypertension, collapse and death. This reaction may be caused by the highly lipid-soluble doxycycline chelating intracellular calcium, resulting in cardiac neuromuscular blockade. 

Minocycline is another commonly prescribed oral antibiotic used in the treatment of moderate to severe acne vulgaris. It is more effective than tetracycline because of greater lipid solubility and enhanced penetration into tissne and sebaceons foUicles. It is dosed similarly to doxycycline (100 mg/day or 50 mg twice daily) and on an indefinite basis in selected patients. 

Doxycycline is more lipid-soluble than other tetracyclines and less dependent on renal elimination more than 50% of the drug is eliminated in the feces. 

The absorption of tetracyclines from the G1 tract is non-uniform. Up to 30% of chlortetracycline is absorbed. The absorption for tetracycline, oxytetracycline, and demeclo-cycline ranges between 60 and 80%, whereas as much as 90 to 100% of doxycycline and minocycline is absorbed. The absorption of tetracyclines is impaired by divalent cations (calcium, magnesium, and ferrous iron), by aluminum, and by extremely alkaline pHs. Tetracyclines are distributed widely throughout the body fluid, cross the placental barrier, and can accumulate in growing bones. The concentrations of chlortetracycline in spinal fluid are only one fourth of those in plasma. Minocycline, a more lipid-soluble tetracycline, reaches a high concentration in tears and saliva and can eradicate the meningococcal carrier state. The tetracyclines are metabolized in the liver and excreted mainly by the bile and urine. The concentrations of tetracyclines in the bile are ten times higher than those in serum. 

Doxycycline and minocycline, because they are lipid-soluble and are not cleared by the kidney. 

Drugs of the tetraeycline group are amphoteric, forming salts with both acids and bases. They are used as parent compounds (e.g., oxytetracycline dihydrate) or as salts (e.g., oxytetracycline hydrochloride). Their lipid solubilities range from moderate (oxytetracycline and chlortetracycline) to high (doxycycline and minocycline), so that they are able to traverse cell membranes moderately or readily. The former two drugs are natural tetracyclines, while the latter two are semi-synthetic. 

An example is the increase in lipid solubility achieved by chemical modification by tetracycline to give the derivative doxycycline. Doxycycline (Vibramycin) is more efficiently absorbed from the intestine than is tetracycline, partly because of better lipid solubility and partly because of a decreased tendency to form poorly soluble complexes with calcium. 

---