PPARα-Dependent Modulation by Metformin of the Expression of OCT-2 and MATE-1 in the Kidney of Mice.

Metformin is the first-line drug for type 2 diabetes mellitus control. It is established that this drug traffics through OCT-2 and MATE-1 transporters in kidney tubular cells and is excreted in its unaltered form in the urine. Hereby, we provide evidence that points towards the metformin-dependent upregulation of OCT-2 and MATE-1 in the kidney via the transcription factor proliferator-activated receptor alpha (PPARα). Treatment of wild type mice with metformin led to the upregulation of the expression of OCT-2 and MATE-1 by 34% and 157%, respectively. An analysis in a kidney tubular cell line revealed that metformin upregulated PPARα and OCT-2 expression by 37% and 299% respectively. MK-886, a PPARα antagonist, abrogated the OCT-2 upregulation by metformin and reduced MATE-1 expression. Conversely, gemfibrozil, an agonist of PPARα, elicited the increase of PPARα, OCT-2, and MATE-1 expression by 115%, 144%, and 376%, respectively. PPARα knockout mice failed to upregulate both the expression of OCT-2 and MATE-1 in the kidney upon metformin treatment, supporting the PPARα-dependent metformin upregulation of the transporters in this organ. Taken together, our data sheds light on the metformin-induced mechanism of transporter modulation in the kidney, via PPARα, and this effect may have implications for drug safety and efficacy.

Effect of trans-dehydrocrotonin, a 19-nor-clerodane diterpene from Croton cajucara on experimental hypertriglyceridaemia and hypercholesterolaemia induced by Triton WR 1339 (tyloxapol) in mice.

The effect of trans-dehydrocrotonin (t-DCTN) from Croton cajucara Benth. was investigated in mice on Triton WR 1339 (tyloxapol)-induced hypercholesterolaemia and hypertriglyceridaemia. Mice treated with single application of tyloxapol (400 mg/kg, i.p.) demonstrated significantly increased blood levels of total cholesterol and triglycerides at 24 h and 48 h after its injection, compared to normal controls. These increases were found to be markedly suppressed in animals treated orally with 25 and 50 mg/kg t-DCTN or 100 mg/kg gemfibrozil, an established antihypercholesterolaemic drug. These results suggest that t-DCTN may be a suitable candidate for combating pathologies associated with hyperlipaemia.

Effect of dietary lipid-lowering drugs upon plasma lipids and egg yolk cholesterol levels of laying hens.

To evaluate the effect of lipid-lowering agents upon egg quality, reproductive performance, plasma lipids, and egg yolk cholesterol levels, 30-week-old Shaver laying hens were fed a basal diet (commercial ration) supplemented with 0.1% probucol (PROB), 0.025% gemfibrozil (GEMF), or lovastatin at 0.0005% (LOV1), 0.001% (LOV2), or 0.0015% (LOV3) for a 12-week experimental period. It was observed that the supplementation of the drugs did not impair albumen and shell quality. Hen performance was not adversely affected. The depression in triglyceride concentrations approached statistical significance only in LOV2 (38.5%), and total cholesterol was significantly depressed in LOV2 (36.0%), LOV3 (36.8%), PROB (29.6%), and GEMF (30.4%) treatments. Egg cholesterol content, expressed per gram of yolk, was significant lowered in LOV1 (7.5%) and LOV3 (12. 7%).

Effect of gemfibrozil versus lovastatin on increased serum lipoprotein(a) levels of patients with hypercholesterolemia.

The aim of this study was to determine the effect of gemfibrozil, compared with lovastatin, in patients with high levels of lipoprotein(a) and on plasma lipid profile. Twenty-seven nondiabetic patients with high levels of plasma lipids and lipoprotein(a), 19 male and eight female, aged 37-68 (mean +/- S.D. 54.2 +/- 7.5) years, were randomly assigned to 2 weeks of treatment with gemfibrozil 600 mg twice daily (14 pts.) or lovastatin 40-80 mg once daily (13 pts.). Patients had fasting plasma total cholesterol levels > or = 6.2 mmol/l, low-density lipoprotein > 4.14 mmol/l and lipoprotein(a) > 0.62 mmol/l. All patients but one had triglycerides > 2.82 mmol/l. There were no statistical differences between both groups in terms of age, sex, clinical diagnosis and previous medication. After 3 months of treatment, gemfibrozil reduced triglycerides (47.9% vs. 24.5%; P < 0.001), very low density lipoprotein (43.9% vs. 24.6%; P < 0.05), lipoprotein(a) (25.3% vs. 4.9%; P < 0.05) and increased high-density lipoprotein (34.4% vs. 11%; P < 0.01) more than lovastatin. Gemfibrozil and lovastatin reduced comparably total cholesterol (21.4% vs. 29.0%; P = NS) and low-density lipoprotein (26.5% vs. 37.3%; P = NS). The plasma levels of high-density lipoprotein and lipoprotein(a) were unchanged significantly by lovastatin. In conclusion, besides well-known efficacy in hyperlipidemia treatment, gemfibrozil also increased high-density lipoprotein and reduced lipoprotein(a), which may have important epidemiologic implications.

Therapeutic effects of bezafibrate and gemfibrozil in hyperlipoproteinaemia type IIa and IIb.

Fifty-nine patients with hyperlipoproteinaemia Type IIa and IIb who had failed to respond to 1-month's dietary therapy were treated over a 4-month period with either bezafibrate (600 mg/day) or gemfibrozil (1200 mg/day) in addition to their diet. Fasting serum lipid (cholesterol, HDL-cholesterol and triglycerides) and blood glucose levels were measured on entry and at monthly intervals, and routine laboratory investigations were carried out before and after treatment to monitor hepatic, renal and haematic tolerance. The results showed that whilst both drugs produced significant reductions from baseline in total cholesterol, LDL-cholesterol and triglyceride levels from Day 30 onwards, the reductions were more marked in the bezafibrate group. There was a trend for HDL-cholesterol levels to increase. Fasting blood glucose levels decreased significantly in the bezafibrate group and to a greater extent than in patients on gemfibrozil. Only 1 patient on bezafibrate did not tolerate bezafibrate whereas 13 patients on gemfibrozil reported side-effects, mainly gastro-intestinal, and 4 had to withdraw from the study during the first or second month.