Tetracyclines bone, accumulation

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). 

Bone. Although bone is a relatively inert tissue, it can accumulate such substances as tetracyclines, lead, strontium, and the antitumor agent cisplatin. These substances may accumulate in bone by absorption onto the bone crystal surface and eventually be incorporated into the crystal lattice. Tetracycline deposition during odontogenesis may lead to a permanent yellow-brown discoloration of teeth, dysplasia, and poor bone development. Lead can substitute for calcium in the bone crystal lattice, resulting in bone brittleness. Bone may become a reservoir for the slow release of toxic substances, such as lead and cisplatin. 

Tetracyclines have the tendency to form chelates with bivalent metal ions. As a consequence of their affinity to calcium, tetracyclines tend to accumulate in the bones of treated animals. Although their chelates with calcium show considerable stability, tetracyclines can be extracted from bones containing these drugs and, therefore, may be present in soups and meals when bones from treated animals are cooked (80, 81). The extractability of chlortetracycline from bone tissue is strongly pH-dependent, being higher at low pH values. This can be easily explained by the dependence of the dissociation constant of the chelate from the pH value. 

Sideroblastic anemia is characterized by the accumulation of iron in the mitochondria of erythroblasts. In a Phase I study in 35 patients with refractory tumors, eight taking CMT-3 developed anemia without leukopenia or thrombocytopenia (54). Three of these patients underwent bone-marrow examination and each had ringed side-roblasts. The authors referred to several cases of aplastic anemia, megaloblastic anemia, and hemolytic anemia in which members of the tetracycline family have been implicated. However, they stated that there has been no previous reports of sideroblastic anemia associated with any tetracycline derivative and that the molecular mechanisms by which CMT-3 might cause sideroblastic anemia are unclear. 

Divalent metal ion chelating agents (e.g. tetracyclines) and heavy metals accumulate in bone by adsorption onto the bone-crystal surface and eventual incorporation into the crystal lattice. 

The antibiotic tetracycline has an affinity for bones and teeth. It should never be used in children as its accumulation can damage teeth and stunt growth. 

Tetracyclines accumulate in tooth enamel and bone and are not recommended for use in children (or during pregnancy) because they cause discolouration of the teeth and stunt bone growth. 

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. 

Distribution TetracycUnes distribute widely throughout the body, including urine and prostate. They accumulate in reticuloendotheUal ceUs of the Uver, spleen, and bone marrow, and in bone, dentine, and enamel of unerupted teeth see below). Meningeal inflammation is not required for passage of tetracyclines into the cerebrospinal fluid (CSF). TetracycUnes cross the placenta and enter the fetal circulation and amniotic fluid. Relatively high concentrations are found in breast milk. 

This insolubility not only is inconvenient for the preparation of solutions but also Interferes with blood levels on oral administration. Consequently, the tetracyclines are incompatible with coadministered, multivalent ion-rich antacids and with hematinics, and concomitant consumption of daily products rich in calcium ion also is contraindicated. Further, the bones, of which the teeth are the most visible, are calcium-rich structures at nearly neutral pHs and so accumulate tetracyclines in proportion to the amount and duration... 

Bound residues of tetracyclines may occur in bones of slaughtered animals for months after treatment. Theoretically, these could reach the food chain via contaminated (mechanically deboned) meat or meat and bonemeal. The accumulation of tetracyclines in tissues is illustrated by the findings of Toutain and Raynaud for oxytetracycline in calves (Table 2.8). Concentrations of oxytetracycline were relatively high in liver and kidney compared to the extrapolated zero-time concentration for serum (4.2 mg/1). The time required for residues to deplete to 0.1 mg/1 in serum was 143 hr, considerably shorter than the time required for residues to deplete to 0.1 mg/kg in liver and kidney, but similar to the depletion time for muscle. The data nicely illustrate the importance of tissue elimination half-life in determining decrease to the 0.1 mg/kg concentration despite an almost three-fold higher initial concentration... 

---