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The cerebrospinal fluid (CSF) movement and its influence on substance distribution and elimination from the CSF system have been thoroughly analyzed and discussed in the light of the new hypothesis of CSF physiology. As a result, CSF movement is not presented as a circulation, but a permanent rhythmic systolic-diastolic pulsation in all directions. Such movement also represents the main force of substance distribution inside the CSF system. This distribution occurs in all directions, i.e., in the direction of the imagined circulation, as well as in the opposite direction, and depends on the application site and the resident time of tested substance, where longer resident time means longer distribution distance. Transport mechanisms situated on the microvessels inside the central nervous system (CNS) parenchyma play the key role in substance elimination from the CSF and interstitial fluid (ISF) compartments, which freely communicate. If a certain transport mechanism is not available at one site, the substance will be distributed by CSF movement along the CSF system and into the CNS region where that transport mechanism is available. Pharmacological manipulation suggests that the residence time and the substance travel distance along the CSF system depend on the capacity of transport mechanisms situated on CNS blood capillaries. Physiological absorption of the CSF into the venous sinuses and/or lymphatics, due to their small surface area, should be of minor importance in comparison with the huge absorptive surface area of the microvessel network.

Oral delivery of peptide therapeutics as a convenient alternate to injections has been an area of research for the pharmaceutical scientific community for the last several decades. However, systemic delivery of therapeutic peptides via the oral route has been a daunting task due to the low pH denaturation of the peptides in the stomach, enzymatic instability, and poor transport across the tight junctions resulting in very low bioavailability. The low bioavailability is accompanied by large intra- and inter-subject variability leading to translational issues, preventing the development of successful peptide therapeutics. The inter-subject variability leads to large differences in pharmacologic responses in individuals and thus the dose required to produce therapeutic effect could vary between individuals making the development of drug product a very difficult task. A substantial amount of research has been (and continues to be) performed with a focus on getting acceptable absorption and reproducible results. Nonetheless, the high variability and low bioavailability during oral administration of peptides is still a work in progress and under-explored in a systematic way. While there are several review articles and scattered publications that discuss potential technologies for oral peptide delivery, a detailed look into the physiological challenges and absorption barriers which are a hindrance to successful clinical translation, is lacking. Herein, we have analyzed the physiological barriers within the gastrointestinal (GI) tract that are the root causes for the low bioavailability and high variability of oral delivery of peptides in humans. In particular, we have taken a detailed look at the key influencing factors such as the nature of various GI tract parameters, components of the GI tract that influences the uptake, site of absorption, pH of the gastric and intestinal compartments, food effect, and role of peptidases in affecting oral peptide absorption. Lack of in vitro - in vivo correlations and variability in animal models have also been highlighted as key impediments in understanding the challenges. The unique perspective presented herein for overcoming the physiological absorption barriers, will offer better developability approaches and will positively impact clinical translation of future oral peptide therapeutics. A deep understanding of these effects are vital, given the emergence of microbiome and oral biologic drug delivery that are fast emerging as the next wave of personalized patient centric therapies.

An innovative technology (Physiomimic Technology) has been applied to amino acids (AAs) formulated for patients with phenylketonuria, with the objective of masking AA taste and odor and prolonging AA release in the gut, allowing a physiological absorption. This technology entails that the AAs are processed with functional additives that are able to modify their release and their organoleptic features. Two prototypes, obtained using sodium alginate + ethylcellulose (engP-1) or sodium alginate + ethylcellulose + glyceryl dibehenate (engP-2), have been tested for AA prolonged release versus the same AAs (n-engP) without the application of the Physiomimic Technology. In vitro tests indicated that the technology is able to prolong the release of the engineered AAs versus the free compounds. A crossover in vivo kinetic study in pigs showed reduced peak concentrations (Cmax) and, as expected, similar areas under the concentration/time curve (up to 5 hours) for the engineered products versus the free AAs. Significantly lower Cmax values (P < .01) were attained for essential AAs, large neutral AAs, and branched-chain AAs, indicating that the technology is able to reduce the typical absorption peak of free AAs. Taste and odor masking has been obtained as a consequence of the AA coating. The Physiomimic Technology, applied to free AAs, provided AA mixes with improved organoleptic features and with modified AA kinetics sustaining a more physiological AA absorption.

A previously presented physiologically-based pharmacokinetic model for immediate release (IR) methylphenidate (MPH) was extended to characterize the pharmacokinetic behaviors of oral extended release (ER) MPH formulations in adults for the first time. Information on the anatomy and physiology of the gastrointestinal (GI) tract, together with the biopharmaceutical properties of MPH, was integrated into the original model, with model parameters representing hepatic metabolism and intestinal non-specific loss recalibrated against in vitro and in vivo kinetic data sets with IR MPH. A Weibull function was implemented to describe the dissolution of different ER formulations. A variety of mathematical functions can be utilized to account for the engineered release/dissolution technologies to achieve better model performance. The physiological absorption model tracked well the plasma concentration profiles in adults receiving a multilayer-release MPH formulation or Metadate CD, while some degree of discrepancy was observed between predicted and observed plasma concentration profiles for Ritalin LA and Medikinet Retard. A local sensitivity analysis demonstrated that model parameters associated with the GI tract significantly influenced model predicted plasma MPH concentrations, albeit to varying degrees, suggesting the importance of better understanding the GI tract physiology, along with the intestinal non-specific loss of MPH. The model provides a quantitative tool to predict the biphasic plasma time course data for ER MPH, helping elucidate factors responsible for the diverse plasma MPH concentration profiles following oral dosing of different ER formulations.

Various bone cements based on calcium phosphate have been used as adjuncts for repairing both the craniofacial and axial skeleton. Ideally these materials should provide initial strength and contour for the reconstruction, and be replaced over time by physiological absorption and bony deposition. Although there is evidence from animal models to support this, opportunities for human studies are rare. Here we offer clinical and histological evidence of this process.

Liposcelis bostrychophilus, whether in culture or fasting, was found to maintain the amount of its body water at nearly 66% of its fresh weight while in air of at least 60% relative humidity between temperatures of 7°C and 42°C. In these conditions intervals of body water loss reaching 1 to 2 μg alternated with recovery of the loss by the physiological absorption of water from vapor at a rate many times that of the water loss. In other conditions a loss of one-half of the body water could be survived. The time dependence of a change in the mass or the tritium content of body water was that of a single compartment from which water molecules were cleared by first-order processes, primarily diffusion, having rates in proportion to the momentary mass of body water while water entered from vapor, was metabolically produced, and some evidently was cleared by processes having rates independent of the body water mass. The physiological absorption process was seen to reach its full rate or to stop within minutes, and it was accompanied by a reduced rate of body water clearance. In any particular physical surroundings the body water mass approached a steady-state value with the half-time of the first-order clearance processes. A few measurements of these quantities, over the ranges of temperature and relative humidity, afforded accurate prediction of the recovery time or the longevity in other conditions.

SummaryUsing the rat intestinal loop technic, it was demonstrated that a large part of a physiological dose of Co60-B12 was adsorbed to the mucosal surface in the presence of rat intrinsic factor (IF) at a faster rate than it was without IF, and ethylenediamine-tetraacetate markedly inhibited this in vivo adsorption. The early mucosal adherence of Co60-B12 did not represent transmucosal absorption, and transserosal absorption was further delayed. It was concluded that there are at least 2 kinds of surface adsorption; one represents a phase of physiological absorption involving IF, and the other, a nonabsorptive process.

Dihydrofolate (H 2 PteGlu) or tetrahydrofolate (H 4 PteGlu), given orally, appears in the blood as a Lactobacillus casei -active form of folate—namely, methyltetrahydrofolate (CH 3 H 4 PteGlu). The same dose of folate given intravenously rapidly exchanges with tissue methylfolate. The results indicate that folate is reduced and methylated in the gut wall during its physiological absorption.

It is not our intention to review drug effects in the colon, which was done extensively and profoundly by Forth and Rummel1 and Powell.2 Our contribution will present studies of drug effects on physiological absorption and secretion processes obtained in the intact human colon and based on results of intestinal perfusion studies of the whole colon and measurements of transepithelial electrical potential difference (PD) in the rectosigmoid colon. These are at present the practiced and—regarding perfusion studies—most accurate techniques in the hands of clinicians to directly study drug effects on a local dose-response scale in the intact human colon. Since these methods are relatively new and their use practically limited to clinical research, no extensive data on this topic are yet available.

Gastrointestinal permeability has been studied in a group of clinically proven food-allergic eczematous children and compared with a control group using lactulose and L-rhamnose as probe markers. No significant difference was demonstrated in baseline permeability measurements between eczematous and control children using isotonic or hypertonic oral loading. Similarly after antigen-challenge permeability results showed no significant difference from the controls although two of the ten eczematous children challenged showed increased permeability to lactulose. These findings support the hypothesis that once sensitized the physiological absorption of dietary antigen may be sufficient to maintain an allergic response in the skin.

Folate absorption and transport were studied in young (2 to 3 months) and aged (28 to 30 months) rats. From studies of the rise in serum folate levels after ingestion and transport across everted intestinal segments it was concluded that the absorption of dietary polyglutamyl folates was impaired in aged animals. Simple folates (monoglutamyl pteroates) were utilized equally well in both age groups. Decreased hydrolysis of polyglutamylfolates to simple forms have been observed in the aged group. High folyl conjugase (pteroyl y-glutamyl hydrolase) levels are induced in pancreas as a response to dietary folate intake; the conjugase is secreted into the gut lumen where enzyme levels rise sequentially reaching maximum in the midgut region within 30 to 60 mm after folate ingestion. The rise in serum folate after folate ingestion parallels the rise in luminal folyl conjugase. Pancreatic and luminal conjugases (but not mucosal conjugase) have similar pH optima. It is suggested that dietary folates are preferentially hydrolyzed to absorbable forms by a luminal folyl conjugase which is of pancreatic origin. The overall enzyme levels are much lower in pancreas of the aged rats, leading to reduced availability of absorbable dietary folates and resulting in folate malabsorption in these animals. It is suggested that the intestinal mucosal conjugase does not play a significant role in the physiological absorption of dietary folates. Am J C/in Nuir 1983:37:262-267.

Publisher Summary The large size of the osteoclast, its multinuclearity, and the striated border in contact with absorbing bone form a striking histological picture that suggests that the cells are highly active and expend energy on a large scale. However, even up to the present time, comparatively little is known about their source, function, life span, or ultimate fate, although it is now over a century since their histological features were first described and illustrated. Inquiry into the biology of the osteoclast has passed through two main epochs and has at present entered a third. The typical osteoclast is a large, multinucleated cell, characteristically found on or near bone in process of absorption. This can be physiological, as for instance in the normal modelling of bone, or it can be the result of some pathological cause. The bone around the tooth germs in the embryonic jaw provides an excellent example of physiological absorption.