Lead exposure, gestational hypertension and pre-eclampsia: a systematic review of cause and effect.

The association between lead and hypertension in adults was first identified in the early 1980's and it has since been proposed that lead may also have a role in gestational hypertension (GH). This systematic review investigates whether lead may be associated with the development of GH or pre-eclampsia. MEDLINE, Embase and Web of Science were searched from inception to August 2011, using the terms: blood lead levels, pregnancy, pregnancy induced hypertension, gestational hypertension and pre-eclampsia. Nine papers were found. Positive associations between lead and GH or pre-eclampsia were found in six studies. The development of GH or pre-eclampsia may serve as a signal to assess blood lead concentrations in pregnant women, as even low lead concentrations have been shown to negatively impact the neurodevelopment and cognitive abilities of children. Adequate calcium intake throughout the pregnancy and lactation period may assist with reducing lead exposure levels.

Expression, activity and regulation of CYP3A in human and rodent brain.

The importance of cytochrome P450 (CYP) 3A enzymes in human drug metabolism is well established. The function of these enzymes has been characterized extensively in liver and intestinal tissues but much less is known about their expression, regulation and functional activity in the brain. Several lines of evidence point to the presence and function of multiple forms of CYP enzymes, including CYP3A, in both human and rodent brain. Expression studies suggest that CYP3A enzymes show regional differences in their distribution in the brain, where they may play a role in steroid metabolism. They also metabolize many psychoactive drugs and may have a profound effect on their efficacy and safety. This review explores the tissue, cellular, and subcellular expression of CYP3A isoforms in human and rodent brain and provides insight into their functional roles and regulation.

N-Acetylcysteine prevents ifosfamide-induced nephrotoxicity in rats.

BACKGROUND AND PURPOSE: Ifosfamide nephrotoxicity is a serious adverse effect for children undergoing cancer chemotherapy. Our recent in vitro studies have shown that the antioxidant N-acetylcysteine (NAC), which is used extensively as an antidote for paracetamol (acetaminophen) poisoning in children, protects renal tubular cells from ifosfamide-induced toxicity at a clinically relevant concentration. To further validate this observation, an animal model of ifosfamide-induced nephrotoxicity was used to determine the protective effect of NAC. EXPERIMENTAL APPROACH: Male Wistar albino rats were injected intraperitoneally with saline, ifosfamide (50 or 80 mg kg(-1) daily for 5 days), NAC (1.2 g kg(-1) daily for 6 days) or ifosfamide+NAC (for 6 days). Twenty-four hours after the last injection, rats were killed and serum and urine were collected for biochemical analysis. Kidney tissues were obtained for analysis of glutathione, glutathione S-transferase and lipid peroxide levels as well as histology analysis. KEY RESULTS: NAC markedly reduces the severity of renal dysfunction induced by ifosfamide with a significant decrease in elevations of serum creatinine (57.8+/-2.3 vs 45.25+/-2.1 micromol l(-1)) as well as a reduced elevation of beta2-microglobulin excretion (25.44+/-3.3 vs 8.83+/-1.3 nmol l(-1)) and magnesium excretion (19.5+/-1.5 vs 11.16+/-1.5 mmol l(-1)). Moreover, NAC significantly improved the ifosfamide-induced glutathione depletion and the decrease of glutathione S-transferase activity, lowered the elevation of lipid peroxides and prevented typical morphological damages in renal tubules and glomeruli. CONCLUSIONS AND IMPLICATIONS: Our results suggest a potential therapeutic role for NAC in paediatric patients in preventing ifosfamide nephrotoxicity.

The mechanism of the verapamil-digoxin interaction in renal tubular cells (LLC-PK1).

Verapamil, usually given as a racemic mixture, decreases in vivo and in vitro digoxin renal tubular secretion, which is suggested to be mediated by P-glycoprotein, an ATP-dependent multidrug efflux pump. Importantly, the two enantiomers of verapamil have been reported to similarly inhibit P-glycoprotein-mediated transport of chemotherapeutic agents. In this study, we examined effects of enantiomers of verapamil on digoxin transport across an LLC-PK1 cell monolayer, a model of proximal renal tubular cells. The results indicate that verapamil inhibition of digoxin transport is non-stereospecific. Furthermore, the verapamil-digoxin interaction is not competitive. The two drugs may not share a common initial step in the P-glycoprotein-mediated transport.

P-glycoprotein-mediated renal tubular secretion of digoxin: the toxicological significance of the urine-blood barrier model.

We provide direct evidence that verapamil inhibits active digoxin secretion in renal tubular cells (LLC-PK1), and that verapamil increases cellular accumulation of digoxin. These findings suggest that verapamil inhibits the digoxin active secretory transport at the apical membranes, supporting the theory that P-glycoprotein mediates digoxin secretion in the renal tubular cells. Based on existing data on digoxin transport, we present a hypothetical model for the renal handling of digoxin, implying that P-glycoprotein functions as a driving mechanism of a unidirectional "urine-blood" barrier.

Evidence of renal metabolism of ifosfamide to nephrotoxic metabolites.

Nephrotoxicity is a limiting factor in the use of ifosfamide in children. Despite the co-administration of uroprotective agents such as sodium 2-mercaptoethanesulfonate (mesna), ifosfamide chemotherapy is associated with nephropathy characterized by glomerular toxicity and Fanconi syndrome in many children treated with this drug. This is in distinction to cyclophosphamide, an analogue which differs solely by the position of a chloroethyl group, and which is not associated with nephrotoxicity. We hypothesized that ifosfamide is metabolized by cytochrome P450 (CYP) enzymes located in the renal tubular cell to the toxic metabolite chloroacetaldehyde; and, that the higher production of chloroacetaldehyde from ifosfamide than from cyclophosphamide explains the clinical differences in nephrotoxicity. We found that in both pig renal cortical microsomes and whole human kidney microsomes incubated with 1 mM ifosfamide for 3 hr, 2 and 3 dechloroethylifosfamide (DCEI) were produced. Our study provides evidence that porcine and human kidney microsomes are capable of biotransforming ifosfamide to DCEI metabolites that are produced in equimolar amounts with chloroacetaldehyde, indicating that chloroacetaldehyde is locally produced by renal cells as a possible mechanism for nephrotoxicity.

Hypothetical framework for enhanced renal tubular secretion of drugs in cystic fibrosis.

Several clinical studies demonstrate reduced serum concentrations of renally excreted drugs in patients with cystic fibrosis (CF). To explain this phenomenon, we propose a model supporting increased proximal tubular secretion of certain drugs in individuals with CF. We hypothesize that the chloride channel located on the apical surface of renal proximal tubular cells and controlled by the cystic fibrosis transmembrane conductance regulator (CFTR) operates suboptimally in CF patients, and that the abnormal CFTR decreases Cl- reabsorption, resulting in an increased concentration of Cl- in the tubular lumen. We postulate that, in an effort to maintain homeostasis, luminal Cl- moves intracellularly in exchange for organic anions. The result of stimulating this anion exchanger is an increased rate of organic anion secretion by the renal tubule. Hence, due to enhanced tubular secretion, individuals with CF demonstrate increased tubular clearance of organic anion drugs, resulting in lower steady state serum concentrations.

The effects of tetrachloroguaiacol on the growth, survival, and development of the fathead minnow, Pimephales promelas.

Fathead minnow (Pimephales promelas) larvae were exposed for 7 days to tetrachloroguaiacol (TeCG), within 24 h of hatching, at concentrations of 0, 25, 50, 100, 200, 400 microg/L. No significant difference in growth or larval survival was found among treatments. Embryos, within 24 h of fertilization, were also exposed to TeCG at concentrations of 0 and 100 microg/L for 10 days. No significant difference was found between the control and treatment groups for larval survival, body length, body width, or for yolk size of the eleutheroembryos. However, a significant difference was found in the hatching success of the eggs (p = 0.05). Since fathead minnows have been known to spawn in areas close to sites that discharge bleached kraft mill effluent (BKME) which contains TeCG, into receiving waters, naturally occurring populations will likely be affected by the toxicant.

Toxic digoxin-drug interactions: the major role of renal P-glycoprotein.

The clinical use of digoxin is complicated by a large number of drug interactions leading to severe toxicity of the cardiac glycoside. The discovery that digoxin is actively secreted by the renal tubular cell via the p-glycoprotein drug efflux pump has led us to examine whether commonly interacting drugs do so by inhibiting renal tubular secretion of digoxin. We review digoxin-drug interactions which have been studied kinetically in humans, where there are sufficient data on renal clearance of digoxin and GFR.

A model for the prediction of digoxin-drug interactions at the renal tubular cell level.

Digoxin-drug interactions are relatively common causes of digitalis toxicity. Recently, the clinical importance of the renal tubular secretion of digoxin has been proven by documenting drug interactions at this level. The authors describe a model using cultured renal tubular cell monolayers that can be used to predict drug interactions with the cardiac glycoside. This model accurately documents known clinical digoxin interactions such as those with verapamil and propafenone. The common feature of these interactions is that they involve P-glycoprotein substrates (e.g., digoxin, vincristine, vinblastine) or inhibitors (e.g., quinidine, cyclosporine). In the case of the newly described interaction of digoxin with itraconazole, the model preceded the emergence of clinical cases.

Young age and the risk for ifosfamide-induced nephrotoxicity: a critical review of two opposing studies.

Ifosfamide has been in use as an effective antineoplastic agent for solid tumors in both children and adults since the late 1960s. Although some adverse effects (e.g. hemorrhagic cystitis) can be overcome by the co-administration of 2-mercaptoethanesulfonate (MESNA), others such as nephrotoxicity cannot. There is a consensus that factors such as the cumulative dose of ifosfamide and concomitant cisplatin administration may influence not only the incidence but also the severity of ifosfamide-induced renal toxicity. Several preliminary studies suggested young age as a risk factor for nephrotoxicity; however, there is little agreement on this. The reasons for this uncertainty may include sample size, study design, dose and differences in renal function assessment. In this review we examine the two largest cohort studies conducted in pediatric patients. One study suggests that ifosfamide-induced renal toxicity is age- related, whereas analysis of the other failed to show age as an important predictor for ifosfamide-induced renal toxicity. The studies differed in design, end-points of toxicity and concomitant drug therapy. Due to the effectiveness of ifosfamide as an antineoplastic agent, it is important that an understanding of the factors that predispose pediatric patients to ifosfamide-induced nephrotoxicity be obtained.

The digoxin-propafenone interaction: characterization of a mechanism using renal tubular cell monolayers.

When propafenone is given with digoxin, digoxin serum concentrations increase. Although the digoxin-propafenone interaction is well known clinically, the mechanism by which propafenone interferes with digoxin elimination is unclear. To test the hypothesis that propafenone or one or both of its two major metabolites, 5-hydroxypropafenone (5-OHP) and N-depropylpropafenone (NDPP), inhibit the P-glycoprotein-mediated net renal tubular secretion of digoxin, we examined the transport of digoxin and the well-studied P-glycoprotein substrate vinblastine across confluent Madin-Darby canine kidney cell monolayers in the absence and presence of propafenone, 5-OHP and NDPP. Propafenone and its two major metabolites significantly inhibit the secretory flux of digoxin and vinblastine (propafenone > 5-OHP >> NDPP). Despite decreases in net transport, cellular digoxin accumulation did not decrease, suggesting that neither propafenone nor its metabolites prohibited digoxin from entering the cells at the basolateral side. NDPP, but not 5-OHP, was detected after 48 hr of incubation of the cells with propafenone alone. When the cells were incubated with propafenone or 5-OHP, apical accumulation of 5-OHP, but neither propafenone nor NDPP, against a concentration gradient was observed. These findings are consistent with the hypothesis that the digoxin-propafenone interaction results from the inhibition of the renal tubular transport of digoxin by propafenone and its metabolites. Our data suggest that propafenone is an inhibitor of P-glycoprotein, whereas 5-OHP is a possible substrate.

Modeling of P-glycoprotein-involved epithelial drug transport in MDCK cells.

P-glycoprotein (P-gp) on the apical membranes of epithelial cells is known as a drug efflux pump. However, unclear is its integral quantitative role in the overall epithelial drug transfer, which also involves distinct diffusion processes in parallel and sequence. We used a simple three-compartment model to obtain kinetic parameters of each drug transfer mechanism, which can quantitatively describe the transport time courses of P-gp substrates, digoxin and vinblastine, across P-gp-expressing MDCK cell monolayers grown on permeable filters. Our results show that the model, which assumes a functionally single drug efflux pump in the apical membrane with diffusion across two membranes and intercellular junctions, is the least complex model with which to quantitatively reproduce the characteristics of the data. Interestingly, the model predicts that the MDCK apical membranes are less diffusion permeable than the basolateral membrane for both drugs and that the distribution volume of vinblastine is 10-fold higher than that of digoxin. Additional experiments verified these model predictions. The modeling approach is feasible to quantitatively describe overall kinetic picture of epithelial drug transport. Further model refinement is necessary to incorporate other modes of drug transport such as transcytosis. Also, whether P-gp solely accounts for the pump function in this model awaits more studies.

The role of the placenta in variability of fetal exposure to cocaine and cannabinoids: a twin study.

There is wide variability in the reported adverse fetal effects of cocaine and cannabinoids. The causes of this variability are largely unknown. We hypothesized that variability in placental handling of drugs affect fetal exposure. We used twin pregnancies as a paradigm to address the role of the placenta in this variability. We analyzed hair or meconium samples taken from dizygotic and monozygotic twins exposed in utero to illicit drugs. Out of 12 pairs, 5 had negative levels in both twins, and seven pairs of twins had chemical evidence of fetal exposure to cocaine (n = 5) or cannabinoids (n = 2). The one known monozygotic pair of twins had almost identical levels of cocaine. In contrast, the six dizygotic pairs had large disparities in either cocaine or cannabinoid concentrations. In three of these six dizygotic pairs, levels of cocaine (n = 2) or canabinoids (n = 1) were undetectable in one twin while positive in the other. Given that twins are theoretically exposed to similar maternal drug levels, our findings suggest that the placenta may have a major role in modulating the amounts of drug reaching the fetus.

Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac)

OBJECTIVE: To compare pregnancy outcome following first-trimester fluoxetine (Prozac) exposure with pregnancy outcome in two matched control groups. Fluoxetine is a new antidepressant used by many young women. Currently, no published data exist on its safety in pregnancy. DESIGN: We prospectively collected and followed up 128 pregnant women exposed to a mean daily dose of 25.8 mg (+/- 13 mg) of fluoxetine during the first trimester and compared pregnancy outcome with two matched groups of women exposed during the first trimester of pregnancy to either nonteratogens or tricyclic antidepressants. RESULTS: Rates of major malformations were comparable within the three groups and did not exceed those expected in the general population. Women treated with fluoxetine had a tendency for increased risk for miscarriage when compared with women exposed to nonteratogens (relative risk, 1.9; 95% confidence interval, 0.92 to 3.92). The rate of miscarriages in the fluoxetine group was comparable with the tricyclic group (13.5% and 12.2% vs 6.8% in the nonteratogens). CONCLUSIONS: Our study suggests that the use of fluoxetine during embryogenesis is not associated with an increased risk of major malformations. Women exposed to both fluoxetine and tricyclic antidepressants tended to report higher rates of miscarriage; further studies will be needed to confirm this observation and to separate the effects of the psychiatric condition from the associated drugs. Long-term studies will be warranted to rule out potential developmental teratology of fluoxetine, which affects a central nervous system neurotransmitter.