Cell delivery tissue loss

Maintenance of red cell volume is critical to having an adequate oxygen supply to the tissues [10]. Healthy individuals finely balance erythropoiesis and erythrocyte loss and maintain constant hematocrit. The glycoprotein hormone erythropoietin is the principal controller of the homeostatic mechanism that links tissue oxygen delivery to red cell production. While hypothesized as early as 1863, unequivocal evidence of erythropoietin was first published in 1953. A few years later, scientists showed that animals subjected to bilateral nephrectomy were unable to mount an erythropoietin response to hypoxia. Indeed, the kidneys produce about 90% of circulating erythropoietin. 

A great number of tissue-specific promoters has been isolated and characterized, and some of these have been used in experimental cancer gene therapy (see Table 1). Obviously, tissue-specific promoters are also active in the normal tissue from which the tumor originated. Unless the loss of these normal cells is acceptable (as in the case of melanocytes), additional specificity mechanisms need to be considered to make the resulting vector useful for a systemic delivery. This can be achieved, for example, by introducing an additional level of specificity, such as a specificity for proliferating cells or a selectivity for other conditions that are characteristic of tumor cells (see later). 

During oral drag absorption, metabolism can occur in the enterocyte cells that line the lumen of the intestine and in the liver before a drug enters the systemic circulation. Loss of drug in either of those locations constitutes first pass elimination . This first-pass effect can be observed for any type of extravascular delivery (nasal, pulmonary, rectal, vaginal, etc.). The magnitude of the first-pass elimination can be quite different in different tissues. However, the most common site for first-pass metabolism is the gut and liver. Once a drug enters the systemic circulation, most of its metabolic elimination occurs in the liver. Consequently, much of the literature on metabolism centers on hepatic metabolism. 

---