Research ArticlesDrug Absorption I: An In Situ Rat Gut Technique Yielding Realistic Absorption Rates
Abstract
A method is reported for studying gastrointestinal drug absorption from isolated gut segments of the anesthetized rat in situ. The experimental technique is simple and utilizes readily available laboratory equipment. The results are closely reproducible and yield absorption rates which are realistic in terms of the known absorption behavior of drugs in humans and intact animals. Disappearance of the drugs from the lumen of the small intestine followed apparent first-order kinetics; and the following half-lives were determined at pH 6: aminopyrine, 32 min.; barbital, 19 min.; haloperidol, 24 min.; prochlorperazine, 23 min.; salicylic acid, 8 min,; and sulfaethidole, 32 min. These absorption rates are much faster than those normally observed in in situ intestinal preparations. Absorption rates from rat stomach in situ, and preliminary data showing a relationship between fasting time and intestinal absorption rates in the rat are also presented.
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Nano lipid based carriers for lymphatic voyage of anti-cancer drugs: An insight into the in-vitro, ex-vivo, in-situ and in-vivo study models
2020, Journal of Drug Delivery Science and TechnologyManagement of cancer by anti-cancer drugs through conventional approaches has presented tough challenges in clinical settings due to non-selective distribution and low bioavailability of cytotoxic drugs causing serious side-effects and multi drug resistance (MDR). Further, lymph node transmission is regarded as preliminary signs of cancer metastasis. Therefore, lipid based nano-carriers (liposomes, functionalized liposomes, solid lipid nanoparticles, polymer-lipid nanoparticles, nano-lipid carriers, self-micro/nanoemulsifying systems, lipid drug conjugate systems and lipid prodrugs) employing lymphatic voyage offer multitude of advantages like selective targeting to localized as well as metastatic conditions, enhanced bioavailability, controlled delivery and management of MDR conditions. For translational objectives lipid based nano-carriers have been tested on various experimental models, viz. in-vitro lipolysis, in-vitro cell permeation (Caco-2 cell line), in-vitro in-vivo correlations, ex-vivo (everted and non-everted gut sac), in-situ intestinal perfusion, in-vivo (small animals and large animals) and chylomicron flow blocking approach. Therefore, we have summarized for the very first time usefulness of all these models with their characteristics, advantages, shortcomings recent modifications and most importantly their applicability in preclinical and clinical settings for nano-lipid carrier based anti-cancer drug delivery with emphasis on lymphatic targeting. We have also reflected the usefulness of in-silico models as a non-invasive approach to predict lymphatic transport of lipid based nano-carriers. We suggest that successful and rapid clinical translation of lymph targeted nano-lipid carriers in cancer therapy can be attained using these models.
Effect of supersaturation on absorption of indomethacin and tadalafil in a single pass intestinal perfusion rat model, in the absence and presence of a precipitation inhibitor
2020, European Journal of Pharmaceutics and BiopharmaceuticsThe effect of the degree of supersaturation (DS) on absorption of the model drugs indomethacin and tadalafil was elucidated in a single-pass intestinal perfusion (SPIP) model in rats. In addition, the performance of the precipitation inhibitor (PI) hydroxypropylmethylcellulose (HPMC) was evaluated when added at a concentration of 0.1% (w/v) to fasted state simulated intestinal fluid (FaSSIF and FaSSIFHPMC) used as perfusion medium.
A supersaturated state was created by a solvent shift method where indomethacin or tadalafil dissolved in dimethyl sulfoxide (DMSO) were administered to a segment of the small intestine, which subsequently was perfused with FaSSIF or FaSSIFHPMC. The perfusate was collected for 60 min, and for one group of rats dosed with 30 mg tadalafil, for 120 min. Blood samples were drawn every 15 min. The solubility of indomethacin and tadalafil in the perfusate was determined. The DS of each drug in the perfusate was calculated by dividing the concentration in the perfusate at selected time points with the solubility. The DS was above one for all timepoints for both drugs, thus showing supersaturation during the time of perfusion. For indomethacin, no improvement of the DS was seen when perfusing with FaSSIFHPMC, compared to FaSSIF. For tadalafil, a higher DS was achieved when perfusing with FaSSIFHPMC compared to FaSSIF. Perfusing the drugs with FaSSIFHPMC resulted in a significantly lower area under the curve (AUC0-60 min) for plasma concentrations of indomethacin, and no increase in the AUC0-60 min of plasma concentrations of tadalafil compared to perfusion with FaSSIF.
The importance of simultaneously estimating the intraluminal DS and absorption of a drug was demonstrated by the SPIP model in the present study. Further, the study highlights the discrepancy between optimal in vitro supersaturation, intraluminal supersaturation and in vivo performance of two poorly soluble drugs, and further emphasizes the importance of optimization of in vitro methods in order to predict in vivo supersaturation and precipitation of drugs.
Rat intestinal drug permeability: A status report and summary of repeated determinations
2019, European Journal of Pharmaceutics and BiopharmaceuticsIntestinal permeability is a key biopharmaceutical variable in pharmaceutical research and development, and regulatory assessment. In situ rat models are often used to predict the corresponding human intestinal permeability data. The rat single-pass intestinal perfusion (SPIP) and intestinal closed loop (ICL) models are commonly applied. The primary objective of this study was to collect, summarize, and evaluate all the available intestinal permeability data for drugs that have been obtained using these two in-situ rat models. The permeability data were also investigated for variability between the experimental designs. The literature survey found 635 permeability determinations for 90 drugs. The studies were performed on the jejunum (n = 284), whole small intestine (n = 111), colon (n = 108), ileum (n = 101), and duodenum (n = 30). All the SPIP (n = 484) and ICL (n = 147) permeability values were summarized in an easily accessible database. There was wide variability in the intestinal permeability to each drug between studies, which was unrelated to the permeability class of the drug. There was no relationship between rat intestinal permeability and luminal pH, luminal drug concentration, rat strain, experimental method, or intestinal region. There was, however, a correlation between permeability values determined in the same laboratory. This report showed that the SPIP and ICL methods are important in situ models for understanding and predicting intestinal drug absorption. However, conclusions based on permeability values sourced from different laboratories may not be reliable. Because each permeability study is unique and because between- and even within-laboratory variability can be substantial, data from individual studies should preferably be interpreted separately.
Covalently crosslinked organophosphorous derivatives-chitosan hydrogel as a drug delivery system for oral administration of camptothecin
2019, European Journal of Pharmaceutics and BiopharmaceuticsHydrogels are widely studied as drug delivery system. In this work we propose the employment of tetrakis(hydroxymethyl)phosphonium chloride as crosslinking agent to obtain covalent hydrogels based on chitosan. These hydrogels are obtained by Mannich reaction between the amino groups of chitosan with the hydroxymethyl groups of the crosslinker molecule. They show a pH sensitive second order swelling kinetic, have low toxicity, are biocompatible, mucoadhesive and allow a modified release of the encapsulated drug, camptothecin, for 48 h. This antitumor drug has been studied as a drug of interest to develop oral chemotherapy administration strategies. According to the obtained results, oral administration of camptothecin through hydrogels would provide low concentrations of drug at the absorption site, avoiding carrier saturation and reducing its intestinal toxicity.
Impact on intestinal permeability of pediatric hyperosmolar formulations after dilution: Studies with rat perfusion method
2019, International Journal of PharmaceuticsThere is no consensus on administering hyperosmolar formulations by mouth to neonates. In 1976, the Committee on Nutrition of the American Academy of Pediatrics published a recommendation of not administer formulations with an osmolarity higher than 400 mOsm/L due to the possible damage to intestine and relationship with necrotizing enterocolitis. Since this recommendation, exists a general trend of reducing osmolality of oral formulations without considering the pharmacokinetics of absorption of the drugs.
The objective of this study was to characterize the permeability values of drugs formulated at different osmolalities by using a well-established rat intestinal perfusion model and to measure the osmolality of the most used formulations in our neonatology unit.
For the osmolality measurement study, most common used oral drugs were selected (compounded formulations and drug products). Osmolality of three dilutions (1:1, 1:4 and 1:8) were measured using a cryoscopic descent osmometer.
Atenolol, caffeine, furosemide, hydrocortisone and paracetamol were selected for the permeability study. Three suspensions were elaborated of each drug (150 mOsm/kg, 300 mOsm/kg and 1500 mOsm/kg). Permeability values and absorption rate coefficients were determined in complete small intestine using in situ “closed loop” perfusion method.
The formulations that resulted to be hyperosmolar (>400 mOsm/kg) were 86% (70% of these proved to be above 1500 mOsm/kg).
The permeability study shown that the osmolality is inversely proportional to the apparent permeability of the drug in the studied drugs. The permeability values obtained with hyperosmolar samples were lower compared to 150 mOsm/kg or 300 mOsm/kg.
Osmolality parameter is of particular relevance in oral drug administration in neonate because the risk of damaging the gastrointestinal tract and because of the risk that modifying osmolality also modifies its permeability, resulting in a potential change in bioavailability.