There is considerable interest in the therapeutic and adverse outcomes of drug interactions at the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). These include altered efficacy of drugs used in the treatment of CNS disorders, such as AIDS dementia and malignant tumors, and enhanced neurotoxicity of drugs that normally penetrate poorly into the brain. BBB- and BCSFB-mediated interactions are possible because these interfaces are not only passive anatomical barriers, but are also dynamic in that they express a variety of influx and efflux transporters and drug metabolizing enzymes. Based on studies in rodents, it has been widely postulated that efflux transporters play an important role at the human BBB in terms of drug delivery. Furthermore, it is assumed that chemical inhibition of transporters or their genetic ablation in rodents is predictive of the magnitude of interaction to be expected at the human BBB. However, studies in humans challenge this well-established paradigm and claim that such drug interactions will be lesser in magnitude but yet may be clinically significant. This review focuses on current known mechanisms of drug interactions at the blood-brain and blood-CSF barriers and the potential impact of such interactions in humans. We also explore whether such drug interactions can be predicted from preclinical studies. Defining the mechanisms and the impact of drug-drug interactions at the BBB is important for improving efficacy of drugs used in the treatment of CNS disorders while minimizing their toxicity as well as minimizing neurotoxicity of non-CNS drugs.

ABSTRACT:Our objective was to evaluate the pharmacokinetics of metformin during pregnancy. Serial blood and urine samples were collected over one steady-state dosing interval in women treated with metformin during early to late pregnancy (n ‫؍‬ 35) and postpartum (n ‫؍‬ 16). Maternal and umbilical cord blood samples were obtained at delivery from 12 women. Metformin concentrations were also determined in breast milk samples obtained over one dosing interval in 6 women. Metformin renal clearance increased significantly in mid (723 ؎ 243 ml/min, P < 0.01) and late pregnancy (625 ؎ 130 ml/min, P < 0.01) compared with postpartum (477 ؎ 132 ml/min). These changes reflected significant increases in creatinine clearance (240 ؎ 70 ml/min, P < 0.01 and 207 ؎ 56 ml/min, P < 0.05 versus 165 ؎ 44 ml/min) and in metformin net secretion clearance (480 ؎ 190 ml/min, P < 0.01 and 419 ؎ 78 ml/min, P < 0.01 versus 313 ؎ 98 ml/min) in mid and late pregnancy versus postpartum, respectively. Metformin concentrations at the time of delivery in umbilical cord plasma ranged between nondetectable (<5 ng/ml) and 1263 ng/ml. The daily infant intake of metformin through breast milk was 0.13 to 0.28 mg, and the relative infant dose was <0.5% of the mother's weight-adjusted dose. Our results indicate that metformin pharmacokinetics are affected by pregnancy-related changes in renal filtration and net tubular transport and can be roughly estimated by the use of creatinine clearance. At the time of delivery, the fetus is exposed to metformin concentrations from negligible to as high as maternal concentrations. In contrast, infant exposure to metformin through the breast milk is low.

Summary:Purpose: Valproic acid (VPA), one of the widely used antiepileptic drugs (AEDs), was recently found to inhibit histone deacetylases (HDACs). HDAC inhibitors of a wide range of structures, such as hydroxamic acids, carboxylic acids, and cyclic tetrapeptides, have various effects on transformed and nontransformed cells, including neuromodulation and neuroprotection. The aim of this study was to assess comparatively the activity of traditional and newer AEDs as HDAC inhibitors.Methods: After incubation of HeLa cells with the tested AEDs, histone hyperacetylation was assessed by immunoblotting with an antibody specific to acetylated histone H4. Direct HDAC inhibition by AEDs was estimated by using HeLa nuclear extract as an HDACs source and an acetylated lysine substrate.Results: We found that in addition to VPA, topiramate (TPM) inhibited HDACs with apparent K i values of 2.22 ± 0.67 mM.Although levetiracetam (LEV) had no direct effect on HDACs, its major carboxylic acid metabolite in humans, 2-pyrrolidinonen-butyric acid (PBA), inhibited HDACs with K i values of 2.25 ± 0.78 mM. The AEDs LEV, phenobarbital, phenytoin, carbamazepine, ethosuximide, gabapentin, and vigabatrin did not inhibit HDACs. The compounds that directly inhibited HDACs also induced the accumulation of acetylated histone H4 in HeLa cells. The effects of TPM and PBA on histone acetylation were significant at 0.25 mM and 1 mM, respectively.Conclusions: We found that in addition to VPA, the newer AED TPM and the major metabolite of LEV, PBA, are able to induce histone hyperacetylation in human cells, although with lower potencies than VPA.

Animal and histopathological studies of human brain support a role for P-glycoprotein (P-gp) in clearance of cerebral β-amyloid (Aβ) across the blood brain barrier (BBB). We tested the hypothesis that BBB P-gp activity is diminished in Alzheimer’s disease (AD) by accounting for AD-related reduction in regional cerebral blood flow (rCBF). Methods We compared P-gp activity in mild AD patients (n=9) and cognitively normal, age-matched controls (n=9) using positron emission tomography (PET) with a labeled P-gp substrate, [11C]-verapamil, and [15O]-water to measure rCBF. BBB P-gp activity was expressed as the [11C]-verapamil radioactivity extraction ratio (ER={[11C]-verapamil brain distributional clearance, K1}/rCBF). Results Compared to controls, BBB P-gp activity was significantly lower in the parietotemporal, frontal, posterior cingulate cortices and hippocampus of mild AD subjects. Conclusion BBB P-gp activity in brain regions affected by AD is reduced and is independent of rCBF. This study improves on prior work by eliminating the confounding effect that reduced rCBF has on assessment of BBB P-gp activity and suggests that impaired P-gp activity may contribute to cerebral Aβ accumulation in AD. P-gp induction/activation to increase cerebral Aβ clearance could constitute a novel preventive or therapeutic strategy for AD.

Optimal development of the embryo and the fetus depends on placental passage of gases, nutrients, hormones, and waste products. These molecules are transferred across the placenta via passive diffusion, carrier-mediated cellular uptake and efflux, and transcytosis pathways. The same mechanisms additionally control the rate and extent of transplacental transfer of drugs taken by the pregnant mother. Essentially all drugs cross the placenta to a certain extent, and some accumulate in the placenta itself at levels that can even exceed those in maternal plasma. Hence, even drugs that are not efficiently transferred across the placenta may indirectly affect fetal development by interfering with placental function. In this article, we describe key properties of the placental barrier and their modulation by medications. We highlight implications for pharmacotherapy and novel approaches for drug delivery in pregnant women and their fetuses.