GI absorption

The GI absorption of the dmg after po adrninistration is slow and variable with estimates ranging from 20—55%. Once absorbed, 96% of the dmg is bound to plasma proteins and other tissues on the body. Whereas peak plasma concentrations may be achieved in 3—7 h, the onset of antiarrhythmic action may occur in 2—3 days or more. This may result, in part, from distribution to and concentration of the dmg in adipose tissue, Hver, spleen, and lungs. Therapeutic plasma concentrations are 1—2 p.g/mL, although there appears to be no correlation between plasma concentration and antiarrhythmic activity. The plasma half-life after discontinuation of the dmg varies from 13—103 days. The dmg is metabolized in the Hver and the principal metaboHte is desethylamiodarone. The primary route of elimination is through the bile. Less than 1% of the unchanged dmg is excreted in the urine. The dmg can also be eliminated in breast milk and through the skin (1,2). 

A third and less common mechanism is production of 1,25-dihydroxyvitamin D by tumor cells (usually lymphoma), which increases GI absorption of calcium and enhances osteoclastic bone resorption. 

D Fleisher, BH Stewart, GL Amidon. Design of prodrugs for improved GI absorption by intestinal enzyme targeting. Methods Enzymol 112 360-381, 1985. 

In order to overcome the limitations of the above drugs, a series of rifamycin derivatives with improved pharmacokinetic (i.e. virtually absence of GI absorption) and pharmacodynamic (i.e. with broad spectrum of antibacterial activity) properties have been synthesized at Alfa Wassermann laboratories [33]. Amongst the different molecules, the compound marked L-105 and later... 

Rifaximin (4-deoxy-4/-methylpyrido[l, 2 -l,2]imidazo-[5,4-c]rifamycin SV, fig. 2) is a synthetic product designed to modify the parent compound, rifamycin, in order to achieve low GI absorption while retaining good antibacterial activity [37]. It is a rifamycin SV derivative, prepared by condensing 2-aminopyridine derivatives to 3-bromorifamycin S (fig. 3) [37-39]. This pyridoimidazo rifamycin SV derivative, which proved to be stable in gastric juice for 24 h, displays a zwitterionic nature at physiological pH [38]. 

The answer is d. (Hardman, pp 816-818.) Digoxin levels can be reduced by 25% with concomitant use of kaolin-pectin by an unknown mechanism that decreases GI absorption. 

Iron-deficiency anemia can be caused by inadequate dietary intake, inadequate GI absorption, increased iron demand (e.g., pregnancy), blood loss, and chronic diseases. 

Cancer and hyperparathyroidism are the most common causes of hypercalcemia. The primary mechanisms are increased bone resorption, increased GI absorption, and decreased renal elimination. 

Hypophosphatemia can be the result of decreased GI absorption, increased urinary excretion, or extracellular to intracellular redistribution. 

Jamali F, Axelson JE. Influence of metoclopramide and propantheline on GI absorption of griseofulvin in rats. J Pharm Sci 1977 66 1540-1543. 

GI absorption of many poorly soluble drugs depends on small intestinal transit, as demonstrated for ketoprofen, nifedipine, haloperidol, miconazole, and others. Small intestinal transit rate and transit time become important factors in drug absorption, particularly when the ratio of dose to solubility is high and dissolution rate is very slow or when the drug is... 

If not in an ER product, a drug is likely to exhibit dissolution-limited absorption if it is poorly soluble in the GI lumen. Usually, identification of a compound with dissolution-limited GI absorption is based on D S ratio (4) when D S is about < 250 mL over the pH range of 1-7.5, the compound is usually considered to have less than ideal lumenal dissolution characteristics (3,5), with 250 mL being a conservative estimate of the total volume of fluids that will be in contact with the dose in the upper GI tract under fasting conditions. However, this approach has several weaknesses ... 

Much else is known about GI absorption. Individuals vary in the extent to which they can absorb the same chemical, and absorption can be influenced by individual factors such as age, sex, health status, and even dietary habits. People who consume large amounts of fiber may absorb less calcium and iron than those who eat less. The GI tract is not fully developed until about 24 months after birth, and infants absorb metals such as lead and certain organic chemicals more readily than do adults. 

Different animal species exhibit differences in GI absorption rates. The extent of GI absorption of lead in rats, for example, can be studied by feeding the animals known amounts of the metal and analyzing the unabsorbed amount that comes through in feces the difference is the amount absorbed. But because of possible species differences it is not possible to conclude that humans will absorb the same amount of lead as the rat. These types of differences complicate evaluation of toxic potential. At the same time, they help to explain why different species of animals respond differently to the same dose of a chemical. 

The antiemetic site of action of tetrahydrocannabinol (THC) Marinot) is unknown, although it appears to affect the central cerebral cortex axis. Relief may occur in individuals refractory to other antiemetics. It is less effective in the elderly, primarily because of its side effects. The antiemetic effect is associated with a high, and this appears to be better tolerated in the young. Sedation is seen in approximately 30% of patients. Ataxia, drowsiness, dry mouth, or orthostatic hypotension may be seen in up to 35% of the older patient population. GI absorption is variable, though blood levels correlate with efficacy. The bioavailabiUty is not as variable if the agent is smoked. The coadministration of prochlorperazine may prevent some of the central nervous system side effects seen with the use of tetrahydrocannabinol. 

Mechanism of Action An antidote that adsorbs (detoxifies) ingested toxic substances, irritants, intestinal gas. Therapeutic Effect Inhibits gastrointestinal (GI) absorption and absorbs intestinal gas. 

Tobacco and rifampin both induce hepatic enzymes, which may decrease the duration of action of the BZs. Grapefruit juice has received recent recognition as a factor in the pharmacokinetics of many drugs. Grapefruit juice slows down the GI absorption of midazolam and also decreases biotransformation, which leads to a delayed onset of effect and an increase in drowsiness (Ameer and Weintraub, 1997). 

Limited data are available on the GI absorption of amphetamine in humans. Beckett and Rowland3 reported serum concentrations of amphetamine in two healthy volunteers after a 15-mg oral dose of the D-isomer. Peak serum concentrations of 48 and 40 ng/ml were achieved at 1.25 h when the volunteers urine was acidified. Slightly higher serum concentrations were observed (52 and 47 ng/ml) if the urine pH conditions were not controlled. Rowland4 observed a peak blood concentration of 35 ng/ml, 2 h after a 10-mg oral dose of D-amphetamine to a healthy 66-kg adult. The half-life for the D-isomer was 11 to 13 h compared with a 39% longer half-life for the L-isomer. If the urine were acidified, excretion was enhanced and the half-lives of both isomers were reduced to approximately 7 h.5 Amphetamine demonstrates a linear one-compartment open model over the dose range 20 to 200 mg. 

Cobalt must be supplied in the diet in its physiologically active form, vitamin B12. GI absorption of cobalt is about 25%, with wide individual variation excretion occurs mainly via the urine. The major part is excreted within days and the rest has a biological half-life of about two years. Originally, the therapy for pernicious anemia was to have patients eat large amounts of liver. The most reliable treatment now is monthly injections of cobalamin. 

Surfactants have been the most investigated chemicals to promote drug absorption from all body tracts. In this section, we will focus on work carried out from the early stages on the enhancing effects of surfactants on drug GI absorption as well as on their interactions with the GI membrane and their toxicity. Systems with multifactorial effects such as emulsions and microemulsions are not the focus of this review. 

Numerous surface-active molecules have been studied as GI absorption promoters in a wide variety of testing conditions, including model membranes, everted intestinal sacs, tissue cultures, intestinal epithelia in diffusion chambers, intact animals, and humans. The physical properties of a chemical enhancer may be strongly dependent on the interactions with the endogenous GI components such as bile salts, pH, and bacteria. Thus the in vitro experiments on enhancing GI absorption are not necessarily predictive of the behavior of the promoter in animals or humans, and we will mainly focus on summarizing results from in vivo studies. 

Other approaches attempted to overcome the obstacle of poor GI absorption of macromolecules include the use of enzyme intestinal inhibitors, chemical derivatization, prodrugs,... 

Therefore, the enhancement of transport is not accompanied by damage to the cells, which is superior to the absorption-enhancing effects of other small molecules, which lead to irreversible changes in the cell membrane and damage to the cell. Thus, much attention has been paid to chitosan as a polymeric substance that enhances GI absorption. 

Carrigan, P.J., and T.R. Bates. 1973. Biopharmaceutics of drugs administered in lipid-containing dosage forms. I. GI absorption of griseofulvin from an oil-in-water emulsion in the rat. J Pharm Sci 62 1476. 

---