Role of two efflux proteins, ABCB1 and ABCG2 in blood-brain barrier transport of bromocriptine in a murine model of MPTP-induced dopaminergic degeneration.

PURPOSE: MPTP-induced dopaminergic degeneration is an experimental model commonly used to explore Parkinson's disease. Cerebral drug transport by ABC transporters in MPTP models has never been reported. METHODS: We have investigated the transport of bromocriptine through the blood-brain barrier (BBB) in a MPTP model to understand the influence of the dopaminergic degeneration on ABCB1 and ABCG2. RESULTS: We have shown that in MPTP treated mice, bromocriptine is widely distributed to brain (2.3-fold versus control, p less than 0.001) suggesting either disruption of BBB or alteration of active efflux of the drug. In situ brain perfusion of [14C]- sucrose and [3H]-inulin did not evidenced a BBB disruption. Studies of ABCB1 and ABCG2 activity showed that MPTP intoxication did not alter their functionality. Conversely, ABCG2 expression studied on brain capillaries from MPTP-treated mice was decreased (1.3-fold, p less than 0.05) and ABCB1 expression increased (1.43-fold, p less than 0.05) as an off-setting of brain transport. CONCLUSIONS: These data demonstrate that MPTP intoxication does not alter the BBB permeability. However, bromocriptine brain distribution is increased in MPTP animals. Hence, MPTP may interact with another transport mechanism such as uptake and/or other efflux transporters. Inflammation and Parkinson's-like lesions induced by MPTP intoxication could lead to modification of drug pharmacokinetics and have clinical consequences, such as neurotoxicity.

ABCB1: the role in Parkinson's disease and pharmacokinetics of antiparkinsonian drugs.

ABCB1/P-glycoprotein (P-gp) is an ATP-dependant transmembrane efflux protein widely expressed in human organs and plays a protective role against endogenous and exogenous substances. It is involved in drug pharmacokinetics affecting drug absorption, disposition and elimination. At the BBB level, due to its luminal localisation, ABCB1 limits drug transport and is important in central detoxification. Inter-individual variability has been described in ABCB1 expression and functionality. Recent work suggests that variability may play a role in the pathogenesis of neurological diseases. Furthermore, ABCB1 expression and/or functionality may modify drug efficacy or increase central adverse events. This paper reviews ABCB1 implication in the pathophysiology of Parkinson's disease and its role in the cerebral distribution of drugs.

Interactions between riluzole and ABCG2/BCRP transporter.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative fatal disease. Drugs used in this disease need to cross the blood-brain barrier (BBB). Only riluzole is approved for ALS treatment. We have investigated riluzole as a breast cancer resistance protein (BCRP) substrate by studying its brain transport in CF1 mdr1a (-/-) mice and its intracellular uptake on BeWo cells (human placental choriocarcinoma cell line). We have also investigated the effect of riluzole on BCRP expression level and on its activity using the prazocin as a test probe for brain transport and intracellular uptake. Assays on mdr1a (-/-) mice and BeWo cells showed a higher uptake of riluzole when pretreated with a BCRP inhibitor. After repeated doses of riluzole, BCRP activity was increased in CF1 mdr1a (-/-) mice, riluzole uptake was decrease and both BCRP expression and activity were increased in BeWo cells. In conclusion, we report in this study that riluzole is transported by BCRP at the BBB level and can enhance its function. These results taken with our previous studies on riluzole and P-glycoprotein show that drug-drug interactions between riluzole and efflux transporters substrates may occur at the BBB level and should be taken into account in future clinical trial design in ALS.

Interactions between antiparkinsonian drugs and ABCB1/P-glycoprotein at the blood-brain barrier in a rat brain endothelial cell model.

Parkinson's disease is a neurodegenerative disorder that requires treatment by dopaminergic agonists, which may be responsible for central side effects. We hypothesized that the efflux transporter ABCB1/P-glycoprotein played a role in brain disposition of antiparkinsonian drugs and could control central toxicity. We aimed to evaluate antiparkinsonian drugs as ABCB1 substrates and/or inhibitors in rat brain endothelial cells GPNT, in order to predict potential clinical drug-drug interactions. Among the antiparkinsonian drugs tested, levodopa, bromocriptine, pergolide and pramipexole were ABCB1 substrates. However, only bromocriptine could inhibit ABCB1 functionality with an IC(50) of 6.71 microM on Rhodamine 123 uptake and an IC(50) of 1.71 microM on digoxine uptake. Thus, bromocriptine at 100 microM is responsible for an increase of levodopa intracellular transport of about 2.05-fold versus control. Therefore, we can conclude that bromocriptine is a potent drug for medicinal interactions in vitro. Hence, in patients with Parkinson's disease, these results may be considered to optimise treatments individually.

Minocycline and riluzole brain disposition: interactions with p-glycoprotein at the blood-brain barrier.

Amyotrophic lateral sclerosis is a neurodegenerative fatal disease. The only drug recognized to increase the survival time is riluzole(RLZ). In animal models, minocycline (MNC) delayed the onset of the disease and increased the survival time (in combination with RLZ). The objective of our work was to study the interactions between RLZ, MNC and the efflux pump p-glycoprotein (p-gp) at the blood-brain barrier. We investigated these two drugs as: (i) p-gp substrates by comparing their brain uptake in CF1 mdr1a (-/-) and mdr1a (+/+) mice, (ii) p-gp modulators by studying their effect on the cerebral uptake of digoxin. mdr1a (-/-) mice showed higher brain uptake of MNC and RLZ than mdr1a (+/+) (in a 1.6- and 1.4-fold, respectively); and in mdr1a (+/+) mice pre-treated with repeated doses of MNC, brain uptake of digoxin was increased. When both drugs were administrated to mdr1a (+/+) mice, MNC increased the brain uptake of RLZ in a 2.1-fold. In conclusion, MNC and RLZ are both p-gp substrates. MNC is also a p-gp inhibitor and increases the brain diffusion of RLZ. In vitro experiments with the GPNT cell line confirmed these results. These interactions should be taken into account in the design of future clinical trials.

Impact of pharmacy validation in a computerized physician order entry context.

BACKGROUND: Computerised physician order entry offers a potential means of reducing prescribing errors, and can also increase the feasibility of pharmacy validation as a secondary filter for eliminating errors. The impacts of these two benefits have never been evaluated in combination. OBJECTIVE: To describe (i) the pharmacists' interventions during validation of drug prescriptions on a computerized physician order entry system, (ii) the impact of these interventions on the prescribing process and (iii) the extent to which computerized physician order entry was responsible for the identified errors. METHOD: Prospective collection of all medication order lines during five days in a tertiary care university hospital using computerized physician order entry for drug prescription. All orders were reviewed by a pharmacist. We described the frequency of pharmacy alerts and their short-term impact on the correction of potential prescribing errors (modification of the prescription). An independent committee reviewed their type and link with the computerized physician order entry system. RESULTS: About 399 (11%) prescription order lines, corresponding to 222 (52%) patients, required a pharmacy alert during the study period. Among the 81 pharmacy alerts targeted to the prescriber, 21 [26% (IC95% = 17-37%)] resulted in a modification of the prescription. Among the 95 potential prescribing error, the independent review committee judged 16 (17%) as potentially life-threatening and attributed 47 (49%) to the use of computerized physician order entry system (unit error, no use of typical order prespecified, prescription inconsistency or other). CONCLUSION: Pharmacy validation produced only a moderate short-term impact on the reduction of potential prescribing errors. However, pharmacy validation may also provide ongoing benefits by identifying necessary improvements in the computerized physician order entry system. Those improvements would allow pharmacists to concentrate on the most relevant interventions.

Interactions between the dopamine agonist, bromocriptine and the efflux protein, P-glycoprotein at the blood-brain barrier in the mouse.

Bromocriptin (BCT) is a dopaminergic receptor agonist, poorly transported through the blood-brain barrier (BBB) and responsible for central side effects. Interactions between BCT and the efflux protein, P-glycoprotein (Pgp), have been described in vitro but nothing is known in vivo nor at the BBB level. At the BBB, in vivo, we investigated BCT as (i) a Pgp substrate by comparing the brain uptake in CF1 mdr1a(-/-) and mdr1a(+/+) mice with or without inhibitors of Pgp (valspodar, elacridar); (ii) a Pgp inducer by looking at the effect of repeated doses of BCT on cerebral uptake of digoxin and comparing it to the effect of dexamethasone and rifampicin; (iii) a Pgp inhibitor by determining the effect of a single dose of BCT on cerebral uptake of digoxin and comparing it to the effect of valspodar. CF1 mdr1a(-/-) mice showed much higher brain uptake of BCT than CF1 mdr1a(+/+) mice and brain uptake of BCT was higher in CF1 mdr1a(+/+) mice pre-treated with valspodar or elacridar indicating that BCT is a Pgp substrate at the BBB level. Brain uptake of digoxin was not modified in CF1 mdr1a(+/+) mice pre-treated with a single dose or repeated doses of BCT, indicating that BCT is neither a Pgp inductor nor a Pgp inhibitor at the BBB in the chosen experimental setting. In vivo, at the mouse BBB level and in our experimental conditions, bromocriptin is a Pgp substrate but is not a Pgp modulator.