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The most common diseases affecting middle-aged and elderly subjects in industrialized countries are multigenetic and lifestyle related. Several attempts have been made to study interactions between genes and lifestyle factors, but most such studies lack the power to examine interactions between several genes and several lifestyle components. The primary objective of the EpiHealth cohort study is to provide a resource to study interactions between several genotypes and lifestyle factors in a large cohort (the aim is 300,000 individuals) derived from the Swedish population in the age range of 45-75 years regarding development of common degenerative disorders, such as cardiovascular diseases, cancer, dementia, joint pain, obstructive lung disease, depression, and osteoporotic fractures. The study consists of three parts. First, a collection of data on lifestyle factors by self-assessment using an internet-based questionnaire. Second, a visit to a test center where blood samples are collected and physiological parameters recorded. Third, the sample is followed for occurrence of outcomes using nationwide medical registers. This overview presents the study design and some baseline characteristics from the first year of data collection in the EpiHealth study.

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ABSTRACT:The hepatobiliary transport and local disposition of rosuvastatin in pig were investigated, along with the impact of concomitant dosing with two known multiple transport inhibitors; cyclosporine and gemfibrozil. Rosuvastatin (80 mg) was administered as an intrajejunal bolus dose in treatments I, II, and III (TI, TII, and TIII, respectively; n ‫؍‬ 6 per treatment). Cyclosporine (300 mg) and gemfibrozil (600 mg) were administered in addition to the rosuvastatin dose in TII and TIII, respectively. Cyclosporine was administered as a 2-h intravenous infusion and gemfibrozil as an intrajejunal bolus dose. In treatment IV (TIV, n ‫؍‬ 4) 5.9 mg of rosuvastatin was administered as an intravenous bolus dose. The study was conducted using a pig model, which enabled plasma sampling from the portal (VP), hepatic (VH), and femoral veins and bile from the common hepatic duct. The biliary recoveries of the administered rosuvastatin dose were 9.0 ؎ 3.5 and 35.7 ؎ 15.6% in TI and TIV, respectively. Rosuvastatin was highly transported into bile as shown by the median AUC bile /AUC VH ratio in TI of 1770 (1640-11,300). Gemfibrozil did not have an effect on the plasma pharmacokinetics of rosuvastatin, most likely because the unbound inhibitor concentrations did not exceed the reported IC 50 values. However, cyclosporine significantly reduced the hepatic extraction of rosuvastatin (TI, 0.89 ؎ 0.06; TII, 0.46 ؎ 0.13) and increased the AUC VP and AUC VH by 1.6-and 9.1-fold, respectively. In addition, the biliary exposure and f e, bile were reduced by Ϸ50%. The strong effect of cyclosporine was in accordance with inhibition of sinusoidal uptake transporters, such as members of the organic anion-transporting polypeptide family, rather than canalicular transporters.Drug-drug interactions (DDIs) involving rosuvastatin that result in increased plasma exposure of rosuvastatin might, in rare cases, result in severe unwanted side effects such as myopathy and possibly rhabdomyolysis (Thompson et al., 2003). A 7.1-and 10.6-fold increase in the plasma exposure (AUC) and maximum plasma concentration (C max ) of a single 10-mg oral rosuvastatin dose was observed in heart transplant patients receiving cyclosporine treatment (75-200 mg b.i.d.) (Simonson et al., 2004). In addition, gemfibrozil (600 mg b.i.d.) increased the AUC and C max of a single 80-mg rosuvastatin dose by 1.88-and 2.21-fold, respectively .These clinically relevant DDIs are considered to involve inhibition of hepatic transport proteins although the in vivo relevant mechanism(s) remains to be elucidated. High hepatic exposure is essential for rosuvastatin, which exhibits its pharmacological effects by inhibiting HMG-Co A reductase, localized to the endoplasmic reticulum of the hepatocyte. Rosuvastatin has an estimated hepatic extraction of 0.63 in humans and the hepatic clearance accounts for approximately 70% of the total plasma clearance (Martin et al., 2003a). OATP1B1 (SLCO1B1) is reported to be the primary transporter involved; however, additional sinusoidal transporters...

ABSTRACT:The aim of this study in pigs was to investigate the local pharmacokinetics of fexofenadine in the intestine and liver by using the pig as a model for drug transport in the entero-hepatobiliary system. A parallel group design included seven pigs (10-12 weeks, 22.2-29.5 kg) in three groups (G1, G2, G3), and a jejunal single-pass perfusion combined with sampling from the bile duct and the portal, hepatic, and superior caval veins was performed. Fexofenadine was perfused through the jejunal segment alone (G1: 120 mg/l, total dose 24 mg) or with two different verapamil doses (G2: 175 mg/l, total dose 35 mg; and G3: 1000 mg/l, total dose 200 mg). The animals were fully anesthetized and monitored throughout the experiment. Fexofenadine had a low liver extraction (E H ; mean ؎ S.E.M.), and the given doses of verapamil did not affect the E H (0.13 ؎ 0.04, 0.16 ؎ 0.03, and 0.12 ؎ 0.02 for G1, G2, and G3, respectively) or biliary clearance. The E H for verapamil and antipyrine agreed well with human in vivo data. Verapamil did not increase the intestinal absorption of fexofenadine, even though the jejunal permeability of fexofenadine, verapamil, and antipyrine showed a tendency to increase in G2. This combined perfusion and hepatobiliary sampling method showed that verapamil did not affect the transport of fexofenadine in the intestine or liver. In this model the E H values for both verapamil and antipyrine were similar to the corresponding values in vivo in humans.The effect of carrier-mediated membrane transport on absorption, first-pass liver extraction, distribution and elimination is not established, because the exact in vivo transport mechanism(s) and its relevance for many drugs that are transport substrates is far from completely understood. Although our knowledge in the field has greatly increased, the integral view on the practical implications of the related findings for ADME research lacks the relevant human in vivo data and a stringent use of data from in vitro models (Meijer and Lennernas, 2005). In addition, investigations of the local liver exposure of drugs and metabolites are considered to be important when assessing dose-dependent drug-induced hepatoxicity (Lee, 2003). Consequently, a model enabling direct determinations to be made of the in vivo kinetics of intestinal and hepatobiliary transport and the metabolism of drugs would be a valuable tool. The use of such a model should increase the understanding of the mechanisms underlying the processes determining the bioavailability and local liver exposure and have an impact on pharmacokinetics and the safety evaluation of drugs. This article describes a novel pig model that combines an intestinal perfusion technique, previously validated in vivo in humans (Lennernas et al., 1992), with sampling from the portal and hepatic vein and bile collection.The transport of a compound across biological membranes often involves multiple transport mechanisms. Hence, the intestinal absorption and disposition of drugs and metabolites is a complex process, gove...