Effects of Ethanol on Intestinal Absorption of Drugs.

The effect of chronic alcohol intake on the intestinal absorption of seven compounds belonging to a homologous series (ciprofloxacin derivatives) was evaluated using an in situ rat gut technique that measures the intrinsic absorption rates of the compounds both in control and chronic alcohol-fed rats. For chronic alcohol treatment, the animals were fed a liquid diet containing ethanol (36% of calories), whereas an isocaloric diet was given to the pair-fed control animals. The biophysical absorption model, relating the intestinal absorption rate constants and partition indexes of the tested compounds, was then established either for control or alcohol-fed animals. Differences were analyzed and tentatively interpreted on the basis of general diffusion principles. Results revealed that, in chronic alcohol-fed animals, hydrophilic homologs are absorbed at a significantly faster rate than in control ones, whereas lipophilic homologs do not change their absorption rate relative to controls. Results demonstrate that the bulk polarity of the microvillous lipoidal membrane is enhanced by chronic ethanol intake, whereas basic features of the aqueous boundary layer are not altered. These observations suggest that the physicochemical properties of the compounds are an important factor in explaining the influence of chronic alcohol intake on passive intestinal absorption of xenobiotics. The possible practical implications of our results are discussed from a speculative viewpoint     

Effects of Insulin-like Growth Factor-I and its Analogue,Long-R 3 -IGF-I,on Intestinal Absorption of 3- O -methyl- d -glucose are Less Pronounced than Gut Mucosal Growth Responses

The relationship between insulin-like growth factor-I (IGF-I) peptide-induced increases in bowel mass and functional improvement is unclear. We utilised three independent methods to investigate the effects of IGF-I peptides on intestinal absorption of the glucose analogue, 3- O -methyl- d -glucose (3MG) in rats. Rats received vehicle, IGF-I or the more potent analogue, long-R 3 -IGF-I via subcutaneously implanted mini-pump, for 7 days, at which time intestinal absorption was assessed by: (1) plasma 3MG appearance following oral gavage, (2) single-pass- or (3) recirculating-perfusion of a jejunal segment. 3MG (320 or 800 &#117 mg) was gavaged on day 7 to rats treated with vehicle, IGR-I or long-R 3 -IGF-I. With the lower 3MG dose, only long-R 3 -IGF-I increased (40%) the initial rate of 3MG appearance in plasma. IGF-I had no significant effect, whilst at the higher 3MG dose neither peptide was effective. Utilising perfusion techniques, long-R 3 -IGF-I, but not IGF-I, significantly increased 3MG uptake per cm of jejunum by up to 69%, although significance was lost when expressed as a function of tissue weight. Long-R 3 -IGF-I, but not native IGF-I, enhanced 3MG absorption from the intestinal lumen, presumably reflecting an increased mucosal mass rather than an up-regulation of specific epithelial glucose transporters.     

L’insuline par voie inhalée : un modèle pour l’absorption systémique pulmonaire ?

European Union has recently approved a form of insulin intended to be inhaled. This innovative presentation has the potential to partially or completely replace the injections and thus facilitate starting insulin therapy which is considered with apprehension and too often differed. On this occasion, we reviewed the issues raised by this pulmonary route for systemic absorption (anatomical and cytological limits, cellular mechanisms, relevant physical parameters, facilitating chemical cofactors, role of tobacco smoking and of common respiratory diseases). The pharmacokinetics of inhaled and injectable insulins are comparable, apart from an appreciably faster absorption of the former and both show the same intra-individual variability. The total biodisponibility is definitely lower with the inhaled way but it is notably increased in smokers. These characteristics can vary according to the inhalation system used. A frequent induced cough, the increase in circulating anti-insulin antibodies and a potentially higher cost are not really determining obstacles. The indications will have to be clearly specified and the long-term inocuity of long term inhalation of such a mitogene especially in children and former smokers remains to be formally proven.     

Suitability of the AUC Ratio as an Indicator of the Pharmacokinetic Advantage in HIPEC

The purpose of this study was to evaluate the area under the concentration-time curve (AUC) ratio as an optimal indicator of the pharmacokinetic advantage during hyperthermic intraperitoneal perioperative chemotherapy. The impact on the AUC ratio on the variables related to the calculation of systemic drug exposure, instillation time, and peripheral drug distribution was evaluated through simulations as well as through a retrospective analysis of studies published in the literature. Both model simulations and the retrospective analysis showed that the 3 variables evaluated had an impact on the AUC ratio value if the complete systemic exposure was not fully considered. However, when that complete systemic exposure was considered, none of these variables affected the AUC ratio value. AUC ratio is not a characteristic parameter of a drug if the calculated systemic drug exposure is not complete. Thus, AUC ratio is not valid for comparing the pharmacokinetic advantage of 2 drugs, and it should not be employed to prove whether a drug can be used in hyperthermic intraperitoneal perioperative chemotherapy safely with regard to toxicity. As an alternative, the study of the absorption rate constant and the bioavailability are proposed as the true and independent parameters that reflect the amount of drug absorbed.     

The Influence of In Vivo Metabolic Modifications on ADMET Properties of Green Tea Catechins–In Silico Analysis

The health effects of green tea are associated with catechins: (?)-epigallocatechin-3-O-gallate (EGCG), (?)-epigallocatechin, (?)-epicatechin-3-O-gallate, and (?)-epicatechin. An understanding of compound absorption, distribution, metabolism, excretion, and toxicity characteristics is essential for explaining its biological activities. Herein, absorption, distribution, metabolism, excretion, and toxicity properties of in vivo detected metabolites of green tea catechins (GTCs) have been analyzed in silico. The influence of metabolic transformations on absorption, distribution, metabolism, and excretion profiles of GTCs corresponds to the effects of size, charge, and lipophilicity, as already observed for other small molecules. Mutagenic, carcinogenic, or liver toxic effects were predicted only for a few metabolites. Similar to galloylated GTCs EGCG and (--)-epicatechin-3-O-gallate, the sulfo-conjugates were predicted to bind at the warfarin binding site. The low free plasma concentration of these derivatives may be consequential to their serum albumin binding. The activity cliff detected for methylated conjugates of EGCG indicates that GTCs' pro-oxidative activity in bound state comes primarily from free hydroxyl groups of the pyrogallol ring B.     

Chemical delivery systems and soft drugs: Retrometabolic approaches of drug design

Inclusion of metabolic considerations in the drug design process leads to significant development in the field of chemical drug targeting and the design of safer drugs during past few years which is a part of an approach now designated as Retro metabolic drug design (RMDD). This approach represents systematic methodologies that integrate structure–activity and structure–metabolism relationships and are aimed to design safe, locally active compounds with an improved therapeutic index. It embraces two distinct methods, chemical delivery systems and a soft drug approach. Present review recapitulates an impression of RMDD giving reflections on the chemical delivery system and the soft drug approach and provides a variety of examples to embody its concepts. Successful application of such design principles has already been applied to a number of marketed drugs like esmolol; loteprednol etc., and many other candidates like beta blockers, ACE inhibitors, alkylating agents, antimicrobials etc., are also under investigation.     

A physiologically based kinetic (PBK) model describing plasma concentrations of quercetin and its metabolites in rats

Biological activities of flavonoids in vivo are ultimately dependent on the systemic bioavailability of the aglycones as well as their metabolites. In the present study, a physiologically based kinetic (PBK) model was developed to predict plasma concentrations of the flavonoid quercetin and its metabolites and to tentatively identify the regiospecificity of the major circulating metabolites. The model was developed based on in vitro metabolic parameters and by fitting kinetic parameters to literature available in vivo data. Both exposure to quercetin aglycone and to quercetin-4′-O-glucoside, for which in vivo data were available, were simulated. The predicted plasma concentrations of different metabolites adequately matched literature reported plasma concentrations of these metabolites in rats exposed to 4′-O-glucoside. The bioavailability of aglycone was predicted to be very low ranging from 0.004%-0.1% at different oral doses of quercetin or quercetin-4′-O-glucoside. Glucuronidation was a crucial pathway that limited the bioavailability of the aglycone, with 95–99% of the dose being converted to monoglucuronides within 1.5–2.5 h at different dose levels ranging from 0.1 to 50 mg/kg bw quercetin or quercetin-4′-O-glucoside. The fast metabolic conversion to monoglucuronides allowed these metabolites to further conjugate to di- and tri-conjugates. The regiospecificity of major circulating metabolites was observed to be dose-dependent. As we still lack in vivo kinetic data for many flavonoids, the developed model has a great potential to be used as a platform to build PBK models for other flavonoids as well as to predict the kinetics of flavonoids in humans.     

Absorption,tissue distribution,tissue metabolism and safety of α-mangostin in mangosteen extract using mouse models

The commercially available herbal products as the form of extract were usually mixtures containing various compounds. In spite of the purported efficacy in each active constituent, the coexisting constituents in the herbal extract might interfere with the efficacy and safety and affect the pharmacokinetic properties of active constituents. To compare for the pharmacokinetic properties of α-mangostin, a major bioactive compound, in mangosteen extract and pure α-mangostin, the pharmacokinetics as well as tissue distribution, in vitro metabolism, plasma protein binding and safety evaluation were conducted in mice because a mouse model is required a small amount of compounds and useful to develop disease models. The absorption of α-mangostin was increased and hepatic metabolism of α-mangostin was decreased in mice treated with mangosteen extract. However, the intestinal metabolism α-mangostin is comparable and still extensive in mice treated with α-mangostin and mangosteen extract. Intraperitorial LC₅₀ of α-mangostin and mangosteen extract was 150 and 231 mg/kg, respectively. These findings may be valuable to explain the different pharmacokinetics and safety of α-mangostin and mangosteen extract. Furthermore, these findings are useful to design the efficacy and safety investigation of α-mangostin or mangosteen extract in mice with disease models or combination therapies to extrapolate into the clinical levels.     

Transport characteristics of isorhamnetin across intestinal Caco-2 cell monolayers and the effects of transporters on it

Flavonoid isorhamnetin occurs in various plants and herbs, and demonstrates various biological effects in humans. This work will clarify the isorhamnetin absorption mechanism using the Caco-2 monolayer cell model. The isorhamnetin transport characteristics at different concentrations, pHs, temperatures, tight junctions and potential transporters were systemically investigated. Isorhamnetin was poorly absorbed by both passive diffusion and active transport mechanisms. Both trans- and paracellular pathways were involved during isorhamnetin transport. Active transport under an ATP-dependent transport mechanism was mediated by the organic anion transporting peptide (OATP); isorhamnetin’s permeability from the apical to the basolateral side significantly decreased after estrone-3-sulfate was added (p < 0.01). Efflux transporters, P-glycoproteins (P-gp), breast cancer resistance proteins (BCRP) and multidrug resistance proteins (MRPs) participated in the isorhamnetin transport process. Among them, the MRPs (especially MRP2) were the main efflux transporters for isorhamnetin; transport from the apical to the basolateral side increased 10.8-fold after adding an MRP inhibitor (MK571). This study details isorhamnetin’s cellular transport and elaborates isorhamnetin’s absorption mechanisms to provide a foundation for further studies.