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| 3. |
- Bergman, Ebba, 1977-, et al.
(författare)
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Effect of a Single Gemfibrozil Dose on the Pharmacokinetics of Rosuvastatin in Bile and Plasma in Healthy Volunteers
- 2010
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Ingår i: Journal of clinical pharmacology. - : Wiley. - 0091-2700 .- 1552-4604. ; 50:9, s. 1039-1049
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Tidskriftsartikel (refereegranskat)abstract
- The effect of a single intrajejunal dose of gemfibrozil (600 mg) on the plasma pharmacokinetics and biliary excretion of a single intrajejunal dose of rosuvastatin (20 mg) was investigated by using a multichannel catheter positioned in the distal duodenum/proximal jejunum in eight healthy volunteers. Bile and plasma samples were collected every 20 min for 200 min, with additional plasma samples being withdrawn for up to 48 hrs. Gemfibrozil did not affect the bioavailability of rosuvastatin, although it increased the apparent absorption phase during the initial 200 minutes (AUC0-200) by 1.56-fold (95%CI: 1.14-2.15). The interaction was less pronounced in this single dose study than in a previous report when gemfibrozil was administered repeatedly, nevertheless, the interaction coincided with the highest exposure to gemfibrozil. The plausible reason why the interaction in this investigation was only minor is the low exposure to gemfibrozil (and its metabolites), suggesting that the total plasma concentration of gemfibrozil needs to be above 20 µM in order to affect the disposition of rosuvastatin. This study demonstrates the value of monitoring the plasma pharmacokinetics of the inhibitor, and not only the drug under investigation, to improve the mechanistic interpretation.
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| 4. |
- Bergman, Ebba, et al.
(författare)
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Pharmacokinetics of gefitinib in humans : the influence of gastrointestinal factors
- 2007
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Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 341:1-2, s. 134-142
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To investigate whether differences in plasma pharmacokinetic profiles of gefitinib between healthy subjects having normal (N; t1/2 > 20 h) and altered (A; t1/2 < 20 h) pharmacokinetic (PK) profiles might be explained by inter-individual variability in gastric emptying and/or precipitation/dissolution of gefitinib in the proximal small intestine. Methods One hundred healthy male subjects were screened to enable identification of subjects with the two PK profiles. Twenty five subjects from the screening were subsequently enrolled in an intubation study where a 250 mg gefitinib dispersion preparation (IRESSA®, AstraZeneca) was administered directly into the stomach. Intestinal fluid samples were withdrawn continuously for 180 min post-dose using the Loc-I-Gut catheter positioned in the jejunum. The crystalline form of gefitinib was determined using Raman microscopy. Results There were no differences between normal and altered subjects with regard to gastric emptying or the precipitation/dissolution of gefitinib in jejunal fluid. Due to difficulties in crystalline identification in the jejunal fluid samples, only the same crystalline form as the dosed form was identified. Conclusions There was no pronounced difference in gastric emptying, precipitation and re-dissolution of gefitinib in proximal human jejunum between normal and altered subjects. Other mechanism(s) are also likely to be important in explaining the inter-individual differences in plasma exposure to gefitinib, such as polymorphism in various metabolic enzymes and/or transport proteins. However, the difference between altered and normal subjects cannot be easily explained and it is likely a multifactorial explanation including low jejunal pH, increased expression of enzymatic and transporter activity and rapid small intestine transit.
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- Bergman, Ebba, 1977-, et al.
(författare)
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The Effect of Acute Administration of Rifampicin and Imatinib on the Enterohepatic Transport of Rosuvastatin In Vivo
- 2010
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Ingår i: Xenobiotica. - : Informa UK Limited. - 0049-8254 .- 1366-5928. ; 40:8, s. 558-568
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Tidskriftsartikel (refereegranskat)abstract
- Hepatobiliary transporters efficiently shunt rosuvastatin from the blood stream, into the hepatocyte, followed by transporter-mediated excretion into the bile ducts. This study aimed at investigating the contribution of sinusoidal versus canalicular transport on the pharmacokinetics of an intrajejunal dose of 80mg rosuvastatin in pigs (control group, n=2+6). The transport inhibitors, rifampicin (20mg/kg, n6) and imatinib (14mg/kg, n6), were administered as 2-h long intravenous infusions. Plasma samples were withdrawn from the portal and hepatic vein simultaneously during 5h along with bile sample collection. Rifampicin reduced the hepatic extraction of rosuvastatin by 35% and the area under the curve in the hepatic vein compartment increased by a factor of 6.3 (95% confidence intervals (CI): 3.132, P value <0.01). The increase in the portal vein compartment was less pronounced than in the hepatic vein, 2.0-fold (95% CI: 1.13.8, P value <0.05), suggesting that the inhibition was predominantly located in the liver rather than in the intestine and suggesting inhibition if sinusoidal transport. In contrast, no effect on the pharmacokinetics of rosuvastatin was observed following concomitant administration with imatinib possibly due to insufficient concentration of the inhibitor inside the hepatocyte. Rifampicin significantly affected the hepatobiliary transport of rosuvastatin, however imatinib did not alter the plasma exposure of rosuvastatin.
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- Bergman, Ebba, 1977-, et al.
(författare)
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The Enterohepatic Disposition of Rosuvastatin in Pigs and The Impact of Concomitant Dosing with Cyclosporine and Gemfibrozil
- 2009
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Ingår i: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 37:12, s. 2349-2358
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Tidskriftsartikel (refereegranskat)abstract
- The hepatobiliary transport and local disposition of rosuvastatin in pig was investigated, along with the impact of concomitant dosing with two known multiple transport inhibitors; cyclosporine and gemfibrozil. 80 mg rosuvastatin 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 two hour intravenous infusion and gemfibrozil as an intrajejunal bolus dose. In Treatment IV (TIV, n=4) was 5.9 mg rosuvastatin 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 recovery of the administered rosuvastatin dose was 9.0±3.5% and 35.7±15.6% in TI and TIV, respectively. Rosuvastatin was highly transported into bile as the median AUCbile/AUCVH ratio was 1770 (1640-11300) in TI. Gemfibrozil did not have an effect on the plasma pharmacokinetics of rosuvastatin, most likely because the unbound inhibitor concentrations did not exceed the reported IC50-values. However, cyclosporine significantly reduced the hepatic extraction of rosuvastatin (TI; 0.89±0.06, TII; 0.46±0.13) and increased the AUCVP and AUCVH by 1.6 and 9.1-fold, respectively. In addition, the biliary exposure and fe, bile were reduced by ≈50%. The strong effect of cyclosporine was in accordance with inhibition of sinusoidal uptake transporters, such as members of the OATP-family, rather than canalicular transporters.
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| 7. |
- Bergman, Ebba, 1977-
(författare)
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The Hepatobiliary Transport of Rosuvastatin In Vivo
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In vivo studies of hepatobiliary disposition are challenging. The hepatobiliary system is complex, as its physiological localization, complex cellular structure with numerous transporters and enzymes, and the interindividual variability in protein expression and biliary flow will all affect the in vivo disposition of a drug under investigation. The research included in this thesis has focused on the involvement of hepatic transport proteins in the hepatobiliary disposition of rosuvastatin. The impact that several transport inhibitors had on the pharmacokinetics of rosuvastatin was investigated in healthy volunteers and in pigs. The effects were considerable, following inhibition of sinusoidal transport proteins by cyclosporine and rifampicin. These inhibitors significantly reduced the hepatic extraction of rosuvastatin by 50 and 35%, respectively, and the plasma exposure increased by factors of 9.1 and 6.3, respectively. Drug-drug interactions (DDI) resulting in markedly higher plasma exposures are important from a drug safety perspective as increased extrahepatic exposure of statins is associated with an increased risk of severe side-effects, such as myopathy which in rare cases could develop into rhabdomyolysis. The DDI caused by cyclosporine and rifampicin can probably be attributed to inhibition of hepatic uptake transporters. In contrast, inhibition of canalicular transporters by imatinib did not significantly affect the pharmacokinetics of rosuvastatin, which suggests that the intracellular concentration of the inhibitor in the hepatocyte was insufficient to affect the transport of rosuvastatin, or that imatinib is not a sufficiently potent inhibitor in vivo. Furthermore, gemfibrozil administered as a single dose into the jejunum in healthy volunteers and pigs did not affect the plasma or biliary pharmacokinetics of rosuvastatin. The previously reported DDI in humans upon repeated dosing with gemfibrozil might be explained by the accumulation of metabolites able to affect the disposition of rosuvastatin. The investigations presented in this thesis conclude that transport proteins are of considerable importance for the hepatobiliary disposition of rosuvastatin in vivo. The Loc-I-Gut catheter can be applied for the investigation of biliary accumulation and to determine bile specific metabolites, however it has limitations when conducting quantitative measurements. In the porcine model, hepatic bile can be collected for up to six hours and enables the determination of the hepatic extraction in vivo.
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| 8. |
- Elenkov, Angel, et al.
(författare)
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Impact of SARS-CoV-2 and Other Upper Respiratory Tract Viral Infections on Reproductive Parameters in Young Healthy Men with Mild Symptoms of Disease
- 2023
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Ingår i: Andrologia. - 0303-4569. ; 2023
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Tidskriftsartikel (refereegranskat)abstract
- Data regarding excretion of SARS-CoV-2 in semen are inconclusive and counseling regarding risk of sexual transmission is still challenging. Our knowledge on the effect of upper respiratory tract infections (URTI) on male reproductive system is also scarce. Apart from negative effect of fever on spermatogenesis virtually no study has been able to compare reproductive parameters in men with COVID-19 or other URTI with predisease data. Eleven men who developed symptoms of URTI during the first and second wave of COVID-19 pandemic and who had preexistent fertility and hormonal data, participated in the study leaving sperm and blood samples. Three additional subjects were recruited among proven SARS-CoV-2 positive male hospital workers (without previous data). SARS-CoV-2 RNA was present in the ejaculate from 2 of 5 (40%) young men with mild COVID-19. In one of them viral particles could be detected in the semen sample 2 weeks after the first sampling. Men with any URTI showed higher LH (p=0.02), lower sperm concentration (p=0.047), and free testosterone (p=0.008) when compared to their samples delivered 10 years earlier. When SARS-CoV-2 positive subjects were compared to subjects with other URTIs, no difference in levels of reproductive parameters or inflammatory markers was seen. In conclusion, SARS-CoV-2 RNA can be present in the ejaculate but does not seem to affect reproductive parameters any more than other viruses. However, mild URTI was shown to affect the sperm concentration, LH, and free testosterone negatively.
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| 9. |
- Humbert, Marion, et al.
(författare)
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Functional SARS-CoV-2 cross-reactive CD4+ T cells established in early childhood decline with age
- 2023
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 120:12
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Tidskriftsartikel (refereegranskat)abstract
- Pre-existing SARS-CoV-2-reactive T cells have been identified in SARS-CoV-2-unexposed individuals, potentially modulating COVID-19 and vaccination outcomes. Here, we provide evidence that functional cross-reactive memory CD4+ T cell immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is established in early childhood, mirroring early seroconversion with seasonal human coronavirus OC43. Humoral and cellular immune responses against OC43 and SARS-CoV-2 were assessed in SARS-CoV-2-unexposed children (paired samples at age two and six) and adults (age 26 to 83). Pre-existing SARS-CoV-2-reactive CD4+ T cell responses targeting spike, nucleocapsid, and membrane were closely linked to the frequency of OC43-specific memory CD4+ T cells in childhood. The functional quality of the cross-reactive memory CD4+ T cell responses targeting SARS-CoV-2 spike, but not nucleocapsid, paralleled OC43-specific T cell responses. OC43-specific antibodies were prevalent already at age two. However, they did not increase further with age, contrasting with the antibody magnitudes against HKU1 (β-coronavirus), 229E and NL63 (α-coronaviruses), rhinovirus, Epstein–Barr virus (EBV), and influenza virus, which increased after age two. The quality of the memory CD4+ T cell responses peaked at age six and subsequently declined with age, with diminished expression of interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor (TNF), and CD38 in late adulthood. Age-dependent qualitative differences in the pre-existing SARS-CoV-2-reactive T cell responses may reflect the ability of the host to control coronavirus infections and respond to vaccination. Copyright © 2023 the Author(s).
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| 10. |
- Lind, Lars, et al.
(författare)
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EpiHealth : a large population-based cohort study for investigation of gene-lifestyle interactions in the pathogenesis of common diseases
- 2013
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 28:2, s. 189-197
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Tidskriftsartikel (refereegranskat)abstract
- 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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