Tissue accumulation of lanthanum as compared to aluminum in rats with chronic renal failure--possible harmful effects after long-term exposure.

BACKGROUND: Lanthanum (La) carbonate is a new treatment for hyperphosphatemia. We tested the effects of oral La carbonate and aluminum hydroxide, respectively, on tissue accumulation and liver function in rats with chronic renal failure (CRF). METHODS: Adult male non-CRF and CRF rats were randomly assigned to 3 groups receiving either standard diet (St.D), or the same diet supplemented with 3% La carbonate (non-CRF La vs. CRF La) or 3% aluminum hydroxide (non-CRF Al vs. CRF Al). RESULTS: After 12 weeks, serum phosphorus was decreased in both CRF La and Al groups. Urinary La and Al excretion was increased in these two groups, and so was liver and bone La content, and liver Al content. Both total body and liver weight were decreased in CRF La and CRF Al rats. Liver cell proliferation was decreased in these groups, while plasma total alkaline phosphatases and alanine aminotransferase were increased. Hepatic total cytochrome p450 content was reduced in CRF La, but not in CRF Al rats. CONCLUSION: Long-term oral La overload in rats with CRF was associated with a decrease in liver (and total body) weight and mild alterations of liver function, as was Al overload, possibly as a consequence of trace element accumulation.

Effects of alpha-linolenic acid vs. docosahexaenoic acid supply on the distribution of fatty acids among the rat cardiac subcellular membranes after a short- or long-term dietary exposure.

BACKGROUND: Previous work showed that the functional cardiac effect of dietary alpha-linolenic acid (ALA) in rats requires a long feeding period (6 months), although a docosahexaenoic (DHA) acid-supply affects cardiac adrenergic response after 2 months. However, the total cardiac membrane n-3 polyunsaturated fatty acid (PUFA) composition remained unchanged after 2 months. This delay could be due to a specific reorganization of the different subcellular membrane PUFA profiles. This study was designed to investigate the evolution between 2 and 6 months of diet duration of the fatty acid profile in sarcolemmal (SL), mitochondrial (MI), nuclear (NU) and sarcoplasmic reticulum (SR) membrane fractions. METHODS: Male Wistar rats were randomly assigned to 3 dietary groups (n = 10/diet/period), either n-3 PUFA-free diet (CTL), or ALA or DHA-rich diets. After 2 or 6 months, the subcellular cardiac membrane fractions were separated by differential centrifugations and sucrose gradients. Each membrane profile was analysed by gas chromatography (GC) after lipid extraction. RESULTS: As expected the n-3 PUFA-rich diets incorporated n-3 PUFA instead of n-6 PUFA in all the subcellular fractions, which also exhibited individual specificities. The diet duration increased SFA and decreased PUFA in SL, whereas NU remained constant. The SR and MI enriched in n-3 PUFA exhibited a decreased DHA level with ageing in the DHA and CTL groups. Conversely, the n-3 PUFA level remained unchanged in the ALA group, due to a significant increase in docosapentaenoic acid (DPA). N-3 PUFA rich diets lead to a better PUFA profile in all the fractions and significantly prevent the profile modifications induced by ageing. CONCLUSION: With the ALA diet the n-3 PUFA content, particularly in SR and SL kept increasing between 2 and 6 months, which may partly account for the delay to achieve the modification of adrenergic response.

Pharmacokinetics of a tri-glucoconjugated 5,10,15-(meta)-trihydroxyphenyl-20-phenyl porphyrin photosensitizer for PDT. A single dose study in the rat.

Photodynamic therapy (PDT) involves a non invasive treatment of small and superficial cancers using a photosensitive drug and light to kill tumoral cells. 5,10,15-meso-tri-(meta-O-beta-D-glucosyloxyphenyl)-20-phenylporphyrin [m-TPP(glu)3] is a new photosensitizer (PS) with more enhanced photocytotoxicity relative to 5,10,15,20-meso-tetra-(meta-hydroxyphenyl) chlorin [m-THPC] (Foscan). It was injected intravenously once to healthy rats at three different doses (0.25, 0.5 and 1 mg kg(-1)) and compared to m-THPC (0.3 mg kg(-1)). Pharmacokinetic parameters for both photosensitizers were derived from plasma concentration-time data using a non-compartmental analysis and a two-compartment pharmacokinetic model. m-TPP(glu)3 is more rapidly eliminated throughout the organism than m-THPC. Its mean plasma clearance is 19 mL h(-1) kg(-1) (6 mL h(-1) kg(-1) for m-THPC), and its mean residence time is 5h (20 h for m-THPC). The area under curve (AUC) and initial mean serum concentration (C0) were found to be proportional to the dose. As for Foscan, no metabolite of m-TPP(glu)3 was detected in plasma. The biodistribution study demonstrates that the most significant amount of m-TPP(glu)3 was concentrated in organs such as lung, liver and spleen which are rich in reticulo-endothelial cells. Maximum concentrations were reached in organs 14 h after IV administration. At 48 h, the photosensitizer was essentially eliminated from all organs. Because of its shorter elimination time, m-TPP(glu)3 is more attractive than m-THPC as a PDT agent since secondary side effects of shorter duration could be expected.

Effect of efavirenz on intestinal p-glycoprotein and hepatic p450 function in rats.

PURPOSE: P-glycoprotein (P-gp) and cytochrome P450 (P450) affect drug disposition. Efavirenz (EFV) is an anti-HIV drug used in combination. Since most anti-HIV medications are substrate and modulators of P-gp and/or P450, we investigated the effects of EFV on intestinal P-gp and hepatic P450 function to predict drug interactions. METHODS: (i) The effect of EFV on rat intestinal P-gp function was studied on everted gut sacs and in situ intestinal perfusion. EFV was orally administered (150 mg/kg) for 6 days. Then, rhodamine 123 was used as a P-gp substrate and verapamil as an inhibitor. P-gp function was evaluated by the difference between rhodamine 123 transport with and without verapamil. (ii) The effect of EFV on rat hepatic P450 metabolism was investigated using hepatic microsomes, prepared from rats pretreated or not with EFV. RESULTS: In everted gut sacs, P-gp function was not modified and in the in situ intestinal perfusion, rhodamine 123 clearance was not affected by EFV. Concentrations of the metabolites, 1-OH midazolam and 4-OH midazolam were higher in EFV pretreated rats than those in the control group. CONCLUSION: EFV should not modify intestinal absorption of co-administered substrates of P-gp, but could decrease plasma concentrations of co-administered drugs metabolized by P450.

Chronic renal failure is associated with increased tissue deposition of lanthanum after 28-day oral administration.

BACKGROUND: Lanthanum (La) carbonate has recently been proposed as an alternative, calcium- and aluminum-free phosphate binder for the treatment of hyperphosphatemia of chronic renal failure (CRF). However, the extent to which CRF enhances tissue La accumulation induced by oral La overload above that observed under conditions of normal renal function remains a matter of debate. In the present study, we examined this issue in two different rat models of CRF. METHODS: In a first series of experiments, adult male Sprague-Dawley rats received either a diet to which 0.3% adenine (wt% in feed) was added to induce CRF ("chemical CRF,"N= 20), or a diet free of adenine (control, N= 16). In a second series of experiments, adult male Sprague-Dawley rats underwent 5/6 nephrectomy in a two-step procedure ("surgical CRF,"N= 24). Half of all CRF and control rats were exposed to dietary La (3% lanthanum carbonate, wt% in feed) for four weeks (La[+] rats), whereas the other half received a placebo (La[-] rats). RESULTS: At the end of this time period, creatinine clearance was 1.51 +/- 0.15 (mean +/- SEM) and 1.45 +/- 0.11 mL/min in La[-] control and La[+] control rats, and declined to 0.22 +/- 0.03 and 0.31 +/- 0.03 mL/min in La[+]-adenine-CRF and La[+]-Nx-CRF rats, respectively. Urinary La excretion was 0.025 +/- 0.010 microg/24 hr in La[-] control rats. It increased to 4.9 +/- 1.2, 17 +/- 3.8, and 77 +/- 18 microg/24 hr in La[+] control, La[+]-adenine-CRF, and La[+]-Nx-CRF rats, respectively. However, only the last value was significantly different from control value. Tissue La concentration was increased in La[+] control rats compared with La[-] control rats. More importantly, tissue La concentration was strikingly higher in La[+]-CRF rats than in La[+] control rats. Thus, liver La (ng/g dry wt) was 1173 +/- 148 in La[+]-adenine-CRF and 1742 +/- 158 in La[+]-Nx-CRF rats, respectively, compared with 385 +/- 29 in La[+] control rats (P < 0.001), and 7.0 +/- 1.4 in La[-] control rats; similarly, bone La was 230 +/- 14 and 288 +/- 26 compared with 81 +/- 8, respectively (P < 0.001), versus 27 +/- 4 in La[-] control rats. Comparable differences were observed in the kidney, skeletal muscle, myocardium, lung, and brain, although to different extents in La[+]-adenine-CRF compared with La[+]-Nx-CRF rats. Finally, liver and kidney weight was significantly reduced in La[+]-adenine-CRF rats compared with La[-]-adenine-CRF rats. CONCLUSION: The oral administration of lanthanum carbonate to normal rats leads to a more than 10-fold increase of tissue La content in at least some organs, including the liver, lung, and kidney. This increase is further enhanced by the uremic state, per se. Plasma levels are a poor indicator of tissue burden. Given the dramatic tissue levels obtained with this rare earth metal given by the oral route, particularly in liver for absolute values, it is probable that the stimulation by CRF is at least partially explained by an increase in intestinal La absorption. The absorptive pathways involved in intestinal La absorption require further study, including possibly enhancing conditions.

Cerebral uptake of mefloquine enantiomers with and without the P-gp inhibitor elacridar (GF1210918) in mice.

1. Mefloquine is a chiral neurotoxic antimalarial agent showing stereoselective brain uptake in humans and rats. It is a substrate and an inhibitor of the efflux protein P-glycoprotein. 2. We investigated the stereoselective uptake and efflux of mefloquine in mice, and the consequences of the combination with an efflux protein inhibitor, elacridar (GF120918) on its brain transport. 3. Racemic mefloquine (25 mg kg(-1)) was administered intraperitoneally with or without elacridar (10 mg kg(-1)). Six to seven mice were killed at each of 11 time-points between 30 min and 168 h after administration. Blood and brain concentrations of mefloquine enantiomers were determined using liquid chromatography. 4. A three-compartment model with zero-order absorption from the injection site was found to best represent the pharmacokinetics of both enantiomers in blood and brain. (-)Mefloquine had a lower blood and brain apparent volume of distribution and a lower efflux clearance from the brain, resulting in a larger brain/blood ratio compared to (+)mefloquine. Elacridar did not modify blood concentrations or the elimination rate from blood for either enantiomers. However, cerebral AUC(inf) of both enantiomers were increased, with a stronger effect on (+)mefloquine. The efflux clearance from the brain decreased for both enantiomers, with a larger decrease for (+)mefloquine. 5. After administration of racemic mefloquine in mice, blood and brain pharmacokinetics are stereoselective, (+)mefloquine being excreted from brain more rapidly than its antipode, showing that mefloquine is a substrate of efflux proteins and that mefloquine enantiomers undergo efflux in a stereoselective manner. Moreover, pretreatment with elacridar reduced the brain efflux clearances with a more pronounced effect on (+)mefloquine.