The Effects of Dose Volume and Excipient Dose on Luminal Concentration and Oral Drug Absorption.

Excipient concentrations in the gastrointestinal luminal fluids can influence the absorption of poorly water-soluble drugs when dosed orally with solubilizing excipients, and poorly permeable drugs when dosed with permeation-enhancing excipients. This report examines how dose volume, excipient dose level, volume of water chaser, and gastric fluid volume influence luminal excipient concentrations, and how these could differ from preclinical species and humans. Gastric concentrations of excipient resulting immediately after dosing typical formulations containing a solubilizing excipient are estimated in preclinical species and humans.

Optimizing Oral Bioavailability in Drug Discovery: An Overview of Design and Testing Strategies and Formulation Options.

For discovery teams working toward new, orally administered therapeutic agents, one requirement is to attain adequate systemic exposure after oral dosing, which is best accomplished when oral bioavailability is optimized. This report summarizes the bioavailability challenges currently faced in drug discovery, and the design and testing methods and strategies currently utilized to address the challenges. Profiling of discovery compounds usually includes separate assessments of solubility, permeability, and susceptibility to first-pass metabolism, which are the 3 most likely contributors to incomplete oral bioavailability.

Absorption enhancers: applications and advances.

Absorption enhancers are functional excipients included in formulations to improve the absorption of a pharmacologically active drug. The term absorption enhancer usually refers to an agent whose function is to increase absorption by enhancing membrane permeation, rather than increasing solubility, so such agents are sometimes more specifically termed permeation enhancers. Absorption enhancers have been investigated for at least two decades, particularly in efforts to develop non-injection formulations for peptides, proteins, and other pharmacologically active compounds that have poor membrane permeability.

Criteria for selecting pharmacokinetic repeat study samples.

The pharmacokinetic (PK) repeat study sample, selected by the study pharmacokineticist, requires repeat bioanalysis because the concentration is incongruous with drug plasma concentration versus time profile. The inconsistency could be due to a number of reasons, including the detectable drug concentration in a predose sample or a sample from a placebo control group or a significant double peak in the terminal phase of an individual plasma concentration versus time profile that is not consistent with the profiles from other subjects in the same dose group. The justification for selecting the PK repeat sample should be clearly documented.

Limited interaction between tacrolimus and P-glycoprotein in the rat small intestine.

The significance of intestinal P-glycoprotein (P-gp) in determining the oral bioavailability of tacrolimus has been still controversial. In this study, we reevaluated the interaction of tacrolimus with P-gp in the rat small intestine, by evaluating its absorption from the rat small intestine and its modulating effect on the absorption of known P-gp substrates (digoxin, methylprednisolone, and vinblastine). Intestinal absorption of tacrolimus itself was as extensive as other P-gp modulators such as cyclosporine and verapamil.

Relationship between loperamide-induced sedative effect and digoxin pharmacokinetics in healthy Japanese subjects.

Purpose: Loperamide-induced suppressive effects on central nervous system closely relate to a lack of or decline in the P-glycoprotein (P-gp) function. The aim of this study was to determine the loperamide-induced sedative effect quantitatively and to investigate possible alterations in the pharmacokinetics of digoxin, a substrate for P-gp, in Japanese subjects.

Methods: Loperamide hydrochloride (2 mg) was administered orally to 26 subjects and the critical flicker-fusion frequency threshold (CFF) values were measured every 30 min separately by portable instrument.

Evaluating barriers to bioavailability in vivo: validation of a technique for separately assessing gastrointestinal absorption and hepatic extraction.

Purpose: The purpose of this study was to develop and validate a method for separately evaluating the roles of gastrointestinal absorption and hepatic extraction as barriers to oral bioavailability (BA). The method was validated using five reference compounds known to have different absorption and hepatic extraction properties. Dose-dependence was also investigated for one reference compound.

Beta-cyclodextrin as a suitable solubilizing agent for in situ absorption study of poorly water-soluble drugs.

To evaluate the intestinal permeability of poorly water-soluble compounds, it is of importance to completely dissolve them in a medium and to avoid precipitation during experiments. This study was undertaken to find an agent possessing a high-solubilizing capacity and exhibiting minimal modulating impact on membrane integrity and absorption systems such as passive diffusion and carrier-mediated permeation. Phenytoin dissolution was compared in the presence of seven solubilizing agents at concentrations of 1, 2, or 5% using a centrifugation method.

In vitro permeation of beta-lactam antibiotics across rat jejunum and its correlation with oral bioavailability in humans.

Aims: To investigate the correlation between in vitro permeation of 11 beta-lactam antibiotics across rat jejunum and their oral bioavailability in humans.

Methods: The absorptive and secretory permeation across rat jejunum was evaluated and apparent permeability coefficients (P(app)) were determined.

Results: A steep, sigmoid-type curve was obtained for the relationship between P(app) in the absorptive permeation and human oral bioavailability.

Formulation and food effects on the oral absorption of a poorly water soluble, highly permeable antiretroviral agent.

DPC 961 is a low-solubility, high-permeability, second-generation non-nucleoside reverse transcriptase inhibitor. The purpose of these studies was to evaluate the effects of drug substance and formulation variables on DPC 961 oral absorption, and to compare fed and fasted state oral absorption. To accomplish this, groups of four to six dogs were dosed with various formulations of DPC 961 under fasted or fed conditions, and DPC 961 pharmacokinetics were examined.

Development and in vivo evaluation of buccal tablets prepared using danazol-sulfobutylether 7 beta-cyclodextrin (SBE 7) complexes.

The aim of the present work was to develop a mucoadhesive controlled-release formulation of danazol-sulfobutylether 7 beta-cyclodextrin (SBE 7) complex and to evaluate the feasibility of improving the bioavailability of danazol via the buccal route. Different types of polymers, polycarbophil (PC) and hydroxypropylmethyl cellulose (HPMC) were mixed with danazol-SBE 7 complex and compressed into tablets. These tablets were evaluated for their dissolution and mucoadhesion properties and for drug absorption in female beagle dogs.

Secretory transport of methylprednisolone possibly mediated by P-glycoprotein in Caco-2 cells.

We recently reported that P-glycoprotein (MDR1) is capable of interfering with the absorption of methylprednisolone in the rat small intestine. This study was undertaken to examine the interaction between methylprednisolone and MDR1 using Caco-2 cells. The permeation of various steroid hormones (hydrocortisone, prednisolone, progesterone, beta-estradiol, and testosterone) was compared.