Poor membrane permeability

Based upon a review of the physical chemical properties of marketed drugs, Lipinski and coworkers have proposed an empirical rule of 5 (20). This rule may help pharmaceutical scientists in reaching an early decision about the potential candidacy for further development of a new chemical entity. The rule states that a chemical candidate is likely to display poor absorption or poor membrane permeability if... 

Drugs in Class III have good aqueous solubility but poor membrane permeability (e.g., bidisomide, bispho-sphonates, captopril, and furosemide). Food and food components would only be expected to influence absorption of drugs in this class if they affected some aspect... 

Class IV drugs have low aqueous solubility and poor membrane permeability and as such are often considered as poor drug candidates for oral administration. Other routes of administration may need to be considered. For example, neomycin falls into this category, and its oral use is to achieve sterilization of the gut. There is too little information about these compounds and the effect of food to offer general observations. 

Figure 1 General pathways through which molecules can actively or passively cross a monolayer of cells. (A) Endocytosis of solutes and fusion of the membrane vesicle with the opposite plasma membrane in an active process called transcytosis. (B) Similar to A, but the solute associates with the membrane via specific (e.g., receptor) or nonspecific (e.g., charge) interactions. (C) Passive diffusion between the cells through the paracellular space. (C, C") Passive diffusion (C ) through the cell membranes and cytoplasm or (C") via partitioning into and lateral diffusion within the cell membrane. (D) Active or carrier-mediated transport of an otherwise poorly membrane permeable solute into and/or out of a cellular barrier.

Limited oral drug bioavailability may be explained by poor membrane permeability, low aqueous solubility in gastrointestinal fluids, or extensive first-pass metabolism in the gastrointestinal tract or liver. Successful lipophilic prodrugs... 

Leuprolide acetate, a highly potent synthetic analogue of LHRH, is a nonapeptide (5-oxo-Pro-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-ethylamide acetate) with a molecular weight of -1200 Da. Leuprolide acetate has shown promise for the treatment of infertility, postmenopausal breast cancer, and prostate cancer. Very low oral bioavailability of leuprolide acetate has led to an interest in using the lung as a site for the systemic delivery of leuprolide. Okada et al. [70] have shown that a mixed micellar solution of leuprolide acetate has only 0.05 % oral bioavailability compared to IV leuprolide acetate. This low oral bioavailability may be attributed to poor membrane permeability as well as to significant enzymatic deactivation in the intestine. 

Due to a combination of poor membrane permeability and metabolism at the site of absorption, rectal bioavailability of peptide and proteins is low. As in other mucosal bioavailability testing, insulin is the most studied polypeptide with respect to rectal absorption. 

The nasal route of delivery is not applicable to all drugs. Polar drugs and some macromolecules are not absorbed in sufficient concentration because of poor membrane permeability, rapid clearance, and enzymatic degradation into the nasal cavity. 

In order to be bioavailable, a drug molecule must be transported through biological membranes. Therefore, molecular properties that correlate with poor membrane permeability (in the absence of active transport) can be used to filter out undesirable molecules. 

Seventy-five percent of drug candidates do not reach the clinical trial phase mainly due to poor pharmacokinetics in animal studies (1). Since so many compounds fail in late stage testing, the current trend is to study the pharmacokinetics of lead compounds as early as possible. One of the most important elements of pharmacokinetics is lipophilicity, or a compound s affinity for fat. Usually, the more water soluble a compound is, the lower its lipophilicity. Low water solubility (high-lipophilicity) compounds have a limited oral bioavailability but are usually easily metabolized. On the other hand, low-lipophilicity compounds have poor membrane permeability since membranes are partly composed of fat. 

Transporters. If the NCEs are substrates for transporters, systemic or target tissue availability of the NCE may become limiting, and consequently influence the pharmacokinetics and pharmacodynamics of the NCE. Efflux transporters such as P-gp present in intestinal epithelia can have negative effects on the bioavailability of NCEs, particularly those that have poor membrane permeability. Whereas for NCEs that have good membrane permeability, efflux transporters do not play as critical role in intestinal absorption since a dose-dependent saturation of the efflux pump... 

The above examples illustrate the sometimes poor permeability observed with amide functional groups in drug compounds and the need to replace them with bioisosteres to overcome these issues. There are other functional groups as well that can lead to poor membrane permeability such as the arginine mimetics, guanidine. 

The choice of steady-state plasma concentrations (Cmax, Cave, and Ctrough) or the concentration in hepatic circulation (Chept inlet,max) of the inhibitor as an estimate of the concentration at the active site of the enzyme (hepatic intracellular concentration). The Chept inlet,max is estimated using Cmax and the rate of absorption after oral administration [Eq. (4.10)]. The DDI may be under- or overpredicted if the drugs are substrates of hepatic transporters (efflux or uptake), show poor membrane permeability, and/or are prone to rapid metabolism. 

It is reasonable to assume that the absorption rate of the complex is negligibly small compared with HCFU alone, owing to the poor membrane permeability and/or poor lipophilicity of the complex. Therefore, greatly enhanced dissolution rate and improved chemical stability of HCFU by CyDs more than may cancel out these negative effects and result in a net increase in the concentration of HCFU available for gastrointestinal absorption. Above results also suggest that the CyD complexes offer a decrease in dose in oral HCFU therapy. 

Newly synthesized prostanoids need to cross the cellular membrane twice when exported from the cytosol and when taken up to reach their cellular targets. At physiological pH, prostanoids exist primarily as charged species, exhibiting poor membrane permeability (S vensson and Yaksh, 2002). There is, however, considerable evidence that prostanoid transport is an active process mediated by a series of transporters. 

Bioavailability problems due to poor/incomplete absorption associated with poor membrane permeability - from gasttointestinal tract, through the blood-brain barrier or through the skin due to high polarity or ionisation. 

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