PRINCIPLES OF TOXICOLOGY - Biology East Borneo

2.3 ABSORPTION 43susceptible to alteration by the actions of intestinal microflora, which are important for digestion ofplant materials resistant to the action of mammalian enzymes. Enzyme systems of the intestinal walland/or the liver may metabolize chemicals before they reach the systemic circulation, the intestinaland/or hepatic first-pass effect, which can result in significant reduction in bioavailability. For example,compared to its 100 percent availability on intravenous injection, the systemic bioavailability in ratsof buprenorphine, an opiate analgesic, was found to be 49 percent when the drug was givenintrahepatoportally and 10 percent when it was given intraduodenally. It can be calculated that after80 percent of the intraduodenal dose had been inactivated in the intestine, half of the surviving 20percent was inactivated in the liver.Another determinant of gastrointestinal absorption is the rate at which foodstuffs pass through theGI tract. If the rate of passage is slowed, the length of time during which the compound is availablefor absorption is increased. Absorption also tends to increase during short periods of fasting but mayfall off after a lengthy fast, probably consequent to a decrease in intestinal blood flow. Other importantinfluences on absorption include the chemical and physical characteristics of the compound, itssolubility under the conditions present in the GI tract, and its interactions with other compounds. Ageand nutritional status of the individual may also affect absorption from the GI tract.SkinThe second major pathway for absorption is the skin. The skin is a very effective barrier to absorption,primarily because of the outermost keratinized layer of thick-walled epidermal cells, the stratumcorneum, which in general is not very permeable to toxicants, although its permeability varies fromlocation to location. Compared with the total thickness of the epidermis and dermis together, thethickness of the stratum corneum is relatively slight, but this barrier is rate-limiting in the process ofabsorption through the skin. There may be slight absorption through sweat glands or hair follicles, butthese structures represent a very small percentage of the total surface area and are not ordinarilyimportant in the process of dermal absorption.All toxicants that penetrate the skin appear to do so by passive diffusion. Lipophilic chemicals aremuch better absorbed through the skin than are hydrophilic chemicals, and the ease with which acompound penetrates the skin is correlated with its partition coefficient.Dermal absorption can be increased in various ways. An increase in capillary blood flow, as inresponse to the demand of a warm environment for efficient heat loss, is associated with increasedpercutaneous absorption. Abrasion, which damages or removes the stratum corneum, greatly increasesthe permeability of the damaged area. The skin is normally partially hydrated; an increase in the degreeof hydration increases permeability and promotes absorption. Certain solvents, such as dimethylsulfoxide (DMSO), also increase skin permeability and facilitate absorption of toxicants.Lipophilic drugs that would suffer extensive first-pass metabolism if given orally can be administereddermally. The glyceryl trinitrate patch used in treatment and prevention of angina is a goodexample.Certain toxicants can produce systemic injury by percutaneous absorption. Hydrocarbon solvents,such as hexane, can produce a peripheral neurotoxicity, and carbon tetrachloride can produce liverinjury. Organophosphate insecticides such as parathion and malathion have caused toxicity and deathsin industrial and field workers after absorption through the skin.LungThe third major site of toxicant absorption is the lung. In occupation-linked toxicology, the lung is avery important route of uptake. Gases and vapors such as carbon monoxide, sulfur dioxide, and volatilehydrocarbons are absorbed through the lung, and liquid or particulate aerosols, such as sulfuric acidaerosols or silica dust, are also deposited and/or absorbed in the lung. With solid and liquid particulates,the site of deposition is critical to the degree of absorption of a compound.