Oral absorption

In terms of activity there seems little to prevent some of these compounds finding a place in therapy, especially those such as SCH 29482, SUN 5555, and FCE 25199 which have oral absorption properties. However, as is the case for the carbapenems, some penems ate extensively metabolized by human renal dehydropeptidase-1 enzyme (144). Although no penem has received approval for clinical use as of this writing, expectations ate high that future research and development will change that. 

The pharmacology of penicillins differs markedly from compound to compound but has been well reviewed (57). The majority of derivatives, including penicillin G and the antipseudomonal penicillins, ate unstable in gastric acid and ate not available orally. The isoxazolyl penicillins ate relatively acid stable but not consistendy well absorbed by the oral route. Nafcillin and oxacillin ate poody absorbed orally cloxacillin, dicloxacillin, and ducloxacillin ate more teUable. Penicillin V, ampicillin, and patticulady amoxicillin ate relatively well absorbed orally. Esters of ampicillin such as bacampicillin, pivampicillin, and talampicillin improve the level of oral absorption of ampicillin to that achieved by amoxicillin. Absorption can be diminished by food after oral adruinistration, however, and peak blood levels, usually achieved after 1 to 2 h, ate somewhat delayed after ingestion of food. 

The acid-instabihty of erythromycin makes it susceptible to degradation in the stomach to intramolecular cyclization products lacking antimicrobial activity. Relatively water-insoluble, acid-stable salts, esters, and/or formulations have therefore been employed to protect erythromycin during passage through the stomach, to increase oral bioavakabihty, and to decrease the variabiUty of oral absorption. These various derivatives and formulations also mask the very bitter taste of macroHdes. 

In Older to improve the poor oral absorption of carbenicillin [4697-36-3] a bpophilic rndanyl ester has been formulated, Geocillin [33331-88-3] (5). Prednisolone [30-24-8] a steroid, is derivatized to its C-21 hemisuccinate sodium salt (6) to make it extremely water-soluble (108). 

Relenza ) in 1999. The polar nature of Relenza precluded significant oral absorption, and therefore an infraoral inhalation drug delivery method was developed that delivered the drug to the primary site of infection. 

Because of its convenience and good patient compliance, oral administration is the most preferred drug delivery form. As a result, much of the attention of in silico approaches is focused on modeling drug oral absorption, which mainly occurs in the human intestine. In general, drug bioavailability and... 

Both influx and efflux transporters are located in intestinal epithelial cells and can either increase or decrease oral absorption. Influx transporters such as human peptide transporter 1 (hPEPTl), apical sodium bile acid transporter (ASBT), and nucleoside transporters actively transport drugs that mimic their native substrates across the epithelial cell, whereas efflux transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP) actively pump absorbed drugs back into the intestinal lumen. 

To correctly predict overall oral absorption, drug metabolism in intestinal epithelial cells by cytochrome P450 enzymes should also be considered. The prediction of drug metabolism has already been covered in detail in Chapter 18. 

Other than the different approaches mentioned above, commercial packages such as GastroPlus (Simulations Plus, Lancaster, CA) [19] and IDEA (LionBioscience, Inc. Cambridge, MA) [19] are available to predict oral absorption and other pharmacokinetic properties. They are both based on the advanced compartmental absorption and transit (CAT) model [20], which incorporates the effects of drug moving through the gastrointestinal tract and its absorption into each compartment at the same time (see also Chapter 22). 

Oral absorption of trichloroethylene in animals is rapid but can be influenced by fasting and the dosing vehicle. Trichloroethylene doses of 5, 10, and 25 mg/kg in 50% aqueous polyethylene glycol 400 were administered to nonfasted rats, and a 10-mg/kg dose was administered to rats that were fasted for 8-10 hours (D Souza et al. 1985). Trichloroethylene was rapidly and completely absorbed in the fasted rats, with peak... 

Experiments demonstrate that oral absorption of trichloroethylene in animals is extensive and metabolism is rapid. A study of F344 rats which were fasted for 8 hours prior to oral dosing by gavage found a rapid appearance of trichloroethylene in the blood which peaked after 0.75 hours, while the peak concentrations of the metabolites trichloroethanol and TCA occurred at 2.5 and 12 hours, respectively (Templin et al. 1995). The same investigators also dosed beagle dogs and found that blood concentrations of trichloroethylene, trichloroethanol, and TCA peaked after 1, 2.5, and 24 hours, respectively. In both species, TCA concentration did not peak until well after the trichloroethylene concentration in blood was below detectable levels (Templin et al. 1995). 

Fig. 2.5 Trendships between oral absorption and permeability/lipophilicity. In reality these relationships are most likely sigmoidal, i.e. more complex than these trends indicate.

Instead of using surrogate measures for oral absorption with a lipophilicity or permeability assay in vitro, oral absorption can also be estimated in silica by using... 

Therefore a continued interest exists in the role of in oral absorption, which often is related to its effect on lipophilicity and solubility. Medicinal chemists can modulate these properties through structural modifications [47]. Various methods to measure pK values have been developed [47-50] and considerable databases are now available. 

Molecular size can be a further limiting factor in oral absorption [54]. The Lipinski Rule-of-5 proposes an upper limit of molecular weight (MW) of500 as acceptable for orally absorbed compounds [25]. High-MW compounds tend to undergo biliary excretion. Size and shape parameters are generally not measured, but rather calculated. A measured property is the so-called cross-sectional area, which is obtained from surface activity measurements [55]. 

MW is often taken as the size descriptor of choice, while it is easy to calculate and is in the chemist s mind. However, other size and shape properties are equally simple to calculate, and may offer a better guide to estimate potential for permeability. Thus far no systematic work has been reported investigating this in detail. Cross-sectional area Ad obtained from surface activity measurements have been reported as a useful size descriptor to discriminate compounds which can access the brain (Ad<80A ) of those that are too large to cross the blood-brain barrier (BBB) [55]. Similar studies have been performed to define a cut-off for oral absorption [56]. 

Van de Waterbeemd, H. Which in vitro screens guide the prediction of oral absorption and volume of distribution Basic Clin. Pharmacol. Toxicol. 2005, 96, 152-165. 

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