Screening novel CNS drug candidates for P-glycoprotein interactions using the cell line iP-gp: In vitro efflux ratios from iP-gp and MDCK-MDR1 monolayers compared to brain distribution data from mice.

Drug efflux by P-glycoprotein (P-gp, ABCB1) is considered as a major obstacle for brain drug delivery for small molecules. P-gp-expressing cell monolayers are used for screening of new drug candidates during early states of drug development. It is, however, uncertain how well the in vitro studies can predict the in vivo P-gp mediated efflux at the blood-brain barrier (BBB). We previously developed a novel cell line of porcine origin, the iP-gp cell line, with high transepithelial resistance and functional expression of human P-gp. The aim of the present study was to evaluate the applicability of the cell line for screening of P-gp interactions of novel drug candidates. For this purpose, bidirectional fluxes of 14 drug candidates were measured in iP-gp cells and in MDCK-MDR1 cells, and compared with pharmacokinetic data obtained in male C57BL/6 mice. The iP-gp cells formed extremely tight monolayers (>15 000 Ω∙cm2) as compared to the MDCK- MDR1 cells (>250 Ω∙cm2) and displayed lower Papp,a-b values. The efflux ratios obtained with iP-gp and MDCK-MDR1 monolayers correlated with Kp,uu,brain values from the in vivo studies, where compounds with the lowest Kp,uu,brain generally displayed the highest efflux ratios. 12 of the tested compounds displayed a poor BBB penetration in mice as judged by Kp,uu less than 1. Of these compounds, nine compounds were categorized as P-gp substrates in the iP-gp screening, whereas analysis of data estimated in MDCK-MDR1 cells indicated four compounds as potential substrates. The results suggest that the iP-gp cell model may be a sensitive and useful screening tool for drug screening purposes to identify possible substrates of human P-glycoprotein.

Outpatient utilization of drugs acting on nervous system: a study from the Republic of Srpska, Bosnia & Herzegovina.

PURPOSE: The aim of this study was to analyse the utilization patterns of drugs acting on the nervous system in the Republic of Srpska, Bosnia & Herzegovina between 2002 and 2008. METHODS: This was a retrospective study aimed at analysing outpatient utilization of drugs reimbursed by the Health Insurance Fund, with a focus on the utilization of drugs acting on the nervous system. Anatomical therapeutic chemical/defined daily dose methodology was used to monitor drug utilization, and the drug utilization 90% (DU90%) method was used to assess drug prescribing. RESULTS: The most highly used drug subgroups were psycholeptics and antiepileptics followed by the psychoanaleptics. Anxyolitics comprised the most prescribed pharmacological subgroup over the whole study period, but a decrease was observed in 2007 and 2008. Following updating of the list with selective serotonin re-uptake inhibitor drugs, particularly sertraline, antidepressant use increased fivefold in 2008 compared to 2006. Tramadol was the predominant opioid analgesics in terms of utilization, while the use of oral morphine was low. Diazepam was the most highly prescribed drug, followed by phenobarbital and carbamazepine. The list update with the new generation drugs was immediately reflected in the DU90% profile. CONCLUSIONS: The observed tendency toward increased total drug utilization observed in our study is comparable to worldwide trends. Implementation of new clinical guidelines for nervous diseases and updating of the list of reimbursable drugs with the addition of new ones contributed to the observed improvement in prescribing patterns in primary healthcare during the study period. The DU90% is shown to be a simple rough method for assessing prescribing quality. More stratified analyses should be performed on a routine basis to ensure a rational use of medicines and a cost-efficient use of limited healthcare resources.