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_Drug

-Epithelium -Primary urine

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-Epithelium -Primary urine

B. Glomerular filtration pH = 7.0 pKa of substance pKa = 7.0

C. Active secretion

D. Tubular reabsorption

Elimination of Lipophilic and Hydrophilic Substances

The terms lipophilic and hydrophilic

(or hydro- and lipophobic) refer to the solubility of substances in media of low and high polarity, respectively. Blood plasma, interstitial fluid, and cytosol are highly polar aqueous media, whereas lipids — at least in the interior of the lipid bilayer membrane — and fat constitute apolar media. Most polar substances are readily dissolved in aqueous media (i.e., are hydrophilic) and lipophilic ones in apolar media. A hydrophilic drug, on reaching the bloodstream, probably after a partial, slow absorption (not illustrated), passes through the liver unchanged, because it either cannot, or will only slowly, permeate the lipid barrier of the hepatocyte membrane and thus will fail to gain access to hepatic biotransforming enzymes. The unchanged drug reaches the arterial blood and the kidneys, where it is filtered. With hydrophilic drugs, there is little binding to plasma proteins (protein binding increases as a function of li-pophilicity), hence the entire amount present in plasma is available for glo-merular filtration. A hydrophilic drug is not subject to tubular reabsorption and appears in the urine. Hydrophilic drugs undergo rapid elimination.

If a lipophilic drug, because of its chemical nature, cannot be converted into a polar product, despite having access to all cells, including metabolically active liver cells, it is likely to be retained in the organism. The portion filtered during glomerular passage will be reabsorbed from the tubules. Reabsorption will be nearly complete, because the free concentration of a lipophilic drug in plasma is low (lipophilic substances are usually largely protein-bound). The situation portrayed for a lipophilic non-metabolizable drug would seem undesirable because phar-macotherapeutic measures once initiated would be virtually irreversible (poor control over blood concentration).

Lipophilic drugs that are converted in the liver to hydrophilic metabolites permit better control, because the lipophilic agent can be eliminated in this manner. The speed of formation of hydrophilic metabolite determines the drug's length of stay in the body.

If hepatic conversion to a polar metabolite is rapid, only a portion of the absorbed drug enters the systemic circulation in unchanged form, the remainder having undergone presystem-ic (first-pass) elimination. When biotransformation is rapid, oral administration of the drug is impossible (e.g., glyceryl trinitate, p. 120). Parenteral or, alternatively, sublingual, intranasal, or transdermal administration is then required in order to bypass the liver. Irrespective of the route of administration, a portion of administered drug may be taken up into and transiently stored in lung tissue before entering the general circulation. This also constitutes pre-systemic elimination.

Presystemic elimination refers to the fraction of drug absorbed that is excluded from the general circulation by biotransformation or by first-pass binding.

Presystemic elimination diminishes the bioavailability of a drug after its oral administration. Absolute bioavail-ability = systemically available amount/ dose administered; relative bioavail-ability = availability of a drug contained in a test preparation with reference to a standard preparation.

Hydrophilic drug

Hydrophilic drug

Lipophilic drug no metabolism

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