Drugs facilitated diffusion

Of the following characteristics, which is unlikely to be associated with the process of facilitated diffusion of drugs ... 

The transport mechanisms that operate in distribution and elimination processes of drugs, drug-carrier conjugates and pro-drugs include convective transport (for example, by blood flow), passive diffusion, facilitated diffusion and active transport by carrier proteins, and, in the case of macromolecules, endocytosis. The kinetics of the particular transport processes depend on the mechanism involved. For example, convective transport is governed by fluid flow and passive diffusion is governed by the concentration gradient, whereas facilitated diffusion, active transport and endocytosis obey saturable MichaeUs-Menten kinetics. 

Although transfer of drugs across the intestinal wall can occur by facilitated transport, active transport, en-docytosis, and filtration, the predominant process for most drugs is diffusion. Thus, the pK of the drug and the pH of the intestinal fluid (pH 5) will strongly influence the rate of drug absorption. While weak acids like phenobarbital (pK 7.4) can be absorbed from the stomach, they are more readily absorbed from the small intestine because of the latter s extensive surface area. 

Extracellular pH and pKa of the drug Although lipid solubility facilitates diffusion of IV anaesthetics across cellular membranes, only the non-ionised form is able to cross these membranes. The ratio of the non-ionised to ionised fraction depends on the pKa of the drug and the pH of the body fluids (see Chapter 2). 

Facilitated diffusion is a carrier-mediated mechanism of transplacental transfer. It is important for endogenous substances, such as glucose. It is also the mechanism for some drugs, e.g. the antibiotic cefalexin. Active transport is a carrier-mediated process that requires energy against an electrochemical or concentration gradient. Amino acids and calcium are transported by this mechanism. Only a few drugs, such as a-methyidopa and 5-fluorouracil, are transferred by active transport. 

Transcellular Drug Absorption—Simple and Facilitated Diffusion... 

FIGURE 1.11 A scheme of the various absorption routes across the intestinal epithelium and cellular barriers to xenobiotics absorption. A, Transcellular absorption (plain diffusion) B, paracellular absorption C, carrier-mediated transcellular absorption D, facilitated diffusion E, the MDR and P-gp absorption barrier and F, endocytosis. (From Hunter, J. and Hirst, B.H., Adv. Drug Deliv. Rev., 25, 129, 1997. With permission.)... 

Phosphonoformic acid (Foscarnet), an antiviral drug, which consists of carboxylic acid and phosphate linked together, was shown to be absorbed in the small intestine by the phosphate carrier-mediated mechanism [154], The transport of folic acid was investigated in biopsy specimens of intestinal mucosa from healthy volunteers. A pH-dependent, active transport of folic acid was found in the proximal small intestine, whereas in the mucosa of the colon, folic acid uptake was driven by a facilitated diffusion, mediated by a low-affinity carrier [155]. The existence of folate receptors in the human colonic mucosa is logical due to the large amounts of folic acid produced by the colonic flora [145],... 

Drugs and other substances that pass through biologic membranes usually do so via passive diffusion, active transport, facilitated diffusion, or some special process such as endocytosis (Fig. 2-2). Each of these mechanisms is discussed here. 

Special carrier molecules exist for certain substances that are important for cell function and too large or too insoluble in lipid to diffuse passively through membranes, eg, peptides, amino acids, glucose. These carriers bring about movement by active transport or facilitated diffusion and, unlike passive diffusion, are saturable and inhibitable. Because many drugs are or resemble such naturally occurring peptides, amino acids, or sugars, they can use these carriers to cross membranes. 

Several polymers were found to fit all or most of the above criteria and were used to prepare the carrier films. Many polymers have been used for this purpose, viz., ethyl cellulose, poly(y-benzyl glutamate), poly(vinyl acetate), cellulose acetate phthalate, and the copolymer of methyl vinyl ether with maleic anhydride. In addition to the base polymers, plasticizers were often needed to impart a suitable degree of flexibility. Plasticizers, which are found to be compatible with polymeric materials include, acetylated monoglycerides, esters of phthalic acid such as dibutyl tartarate, etc. An excipient was usually incorporated into the matrix of the carrier films. The excipients used were water-soluble materials, which are capable of creating channels in the polymer matrix and facilitate diffusion of the drug. PEGs of different molecular weights were used for this purpose. 

The distinction between facilitated diffusion through channels and carrier-mediated transport is somewhat artificial/ but may be justified on the basis of specificity. For example/ 3-lactams in general can pass through nonselective bacterial outer membrane porin (e.g./ OmpF) channels via passive diffusion/ whereas imipenem (and related zwitterionic carbapenems) can also utilize OprD channels/ which preferentially recognize basic amino acids and dipeptides. The identification of mutants that selectively confer imipenem resistance suggests that more intimate protein-drug associations are involved in carrier-mediated transport than in facilitated diffusion/ which may be limited only by pore diameter. 

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