Influence of polyunsaturated fatty acids on Cortisol transport through MDCK and MDCK-MDR1 cells as blood-brain barrier in vitro model.

Abstract Transport across the blood–brain barrier is a relevant factor in the pharmacological action of many drugs and endogenous substances whose action site is located in brain. An overactive P-gp has been suggested to be of relevance for the resistance of the HPA system to be suppressed by glucocorticoids, which is one of the best described biological abnormalities in certain types of depression. PUFA acids have shown clinical efficacy in depressed patients and the hypothesis is that these compounds are able to reduce HPA axis activity as this effect has been shown in animal models of depression. The objective of the present work was (1) to characterize Cortisol transport through MDCK an…

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Aciclovir

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing (biowaiver) for the approval of immediate release (IR) solid oral dosage forms containing aciclovir are reviewed. Aciclovir therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) studies were also taken into consideration in order to ascertain whether a biowaiver can be recommended. According to the Biopharmaceutics Classification System (BCS) and considering tablet strengths up to 400 mg, aciclovir would be BCS Class III. However, in some countries also 800 mg tablets are available which …

Correlation BetweenIn Vitro,In Situ, andIn Vivo Models

Kinetic modelling of passive transport and active efflux of a fluoroquinolone across Caco-2 cells using a compartmental approach in NONMEM.

The purpose was to develop a general mathematical model for estimating passive permeability and efflux transport parameters from in vitro cell culture experiments. The procedure is applicable for linear and non-linear transport of drug with time,10 or10% of drug transport, negligible or relevant back flow, and would allow the adequate correction in the case of relevant mass balance problems. A compartmental kinetic approach was used and the transport barriers were described quantitatively in terms of apical and basolateral clearances. The method can be applied when sink conditions are not achieved and it allows the evaluation of the location of the transporter and its binding site. In this …

How and Where are Drugs Absorbed?

A drug must interact with its receptors at their action sites or therapeutic target to exert its pharmacological or toxic effects. Therefore, the absorption of drug is an essential step which determines pharmacologic effects of drug. This article focuses on the biological barriers that the drug must cross in order to enter the body, drug absorption mechanisms, and influence of physiological characteristics of the administration route on absorption rate and extent. Keywords: drugs; absorption mechanisms; administration routes; passive diffusion; endocytosis

In situ kinetic modelling of intestinal efflux in rats: functional characterization of segmental differences and correlation with in vitro results.

The objective was to devise and apply a novel modelling approach to combine segmental in situ rat perfusion data and in vitro cell culture data, in order to elucidate the contribution of efflux in drug absorption kinetics. The fluoroquinolone CNV97100 was used as a model P-gp substrate. In situ intestinal perfusion was performed in rat duodenum, jejunum, ileum and colon to measure the influence of P-gp expression on efflux. Inhibition studies of CNV97100 were performed in the presence of verapamil, quinidine, cyclosporin A and p-aminohippuric acid. Absorption/efflux parameters were modelled simultaneously, using data from both in situ studies as well as in vitro studies. The maximal efflux …

Progress in the development of early diagnosis and a drug with unique pharmacology to improve cancer therapy

Cancer continues to be one of the major health and socio-economic problems worldwide, despite considerable efforts to improve its early diagnosis and treatment. The identification of new constituents as biomarkers for early diagnosis of neoplastic cells and the discovery of new type of drugs with their mechanistic actions are crucial to improve cancer therapy. New drugs have entered the market, thanks to industrial and legislative efforts ensuring continuity of pharmaceutical development. New targets have been identified, but cancer therapy and the anti-cancer drug market still partly depend on anti-mitotic agents. The objective of this paper is to show the effects of KAR-2, a potent anti-m…

Kinetic modelling of the intestinal transport of sarafloxacin. Studiesin situin rat andin vitroin Caco-2 cells

The absorption kinetics of sarafloxacin, as a model of fluoroquinolone structure, were studied in the rat small intestine and in Caco-2 cells. The objective of the study was to investigate the mechanistic basis of the drug's intestinal transport in comparison with other members of the fluoroquinolone family and to apply a mathematical modelling approach to the transport process. In the rat small intestine, sarafloxacin showed dual mechanisms of intestinal absorption with a passive diffusional component and an absorptive carrier-mediated component. The characteristics of the animal study design made it suitable for population analysis, thus allowing the accurate estimation of transport param…