Browsing by Subject "Pharmacokinetics"

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  • Tuomisto, Jouko; Airaksinen, Riikka; Kiviranta, Hannu; Tukiainen, Erkki; Pekkanen, Juha; Tuomisto, Jouni T. (2016)
    A number of studies have found an association between the concentrations of persistent organic pollutants (POP) and type 2 diabetes. Causality has remained uncertain. This study describes the pharmacokinetic behavior of PCDD/Fs (polychlorinated dibenzo-p-dioxins and dibenzofurans) both in a theoretical model based on elimination rate constants, and in a group of 409 adult surgical patients with known PCDD/F concentrations and dietary information. A model assuming 10% annual decrease in past PCDD/F intake, predicted the measured profile of TEQ (toxic equivalents) in the patient population fairly well. The dominant determinant of PCDD/F level was age, and the level in patients was also associated with consumption of animal source products. Predicted daily intakes correlated with diet, but also with body mass index (BMI), indicating that high BMI was preceded by high consumption of foods containing PCDD/Fs. The results suggest that a third factor, e. g. high intake of animal source foods, could explain both higher levels of POPs in the body and higher incidence of type 2 diabetes, and BMI is not sufficient in describing the confounding caused by diet. Thus, to fully address the causality between POPs and type 2 diabetes, careful studies considering the pharmacokinetics of the studied compounds, and including the analysis of food consumption, are needed. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Vapaatalo, Heikki (2016)
  • Kaartinen, Taavi (Helsingin yliopisto, 2018)
    In vitro studies have shown that esomeprazole, the S-isomer of omeprazole, is a metabolism dependent inhibitor (MDI) of cytochrome P450 2C19, an essential drug-metabolizing enzyme. In this study, we characterized the effects of esomeprazole in vivo on CYP2C19, 3A4, and 1A2 using pantoprazole, midazolam, and caffeine, respectively, as probe drugs. In addition, we estimated the half-life of CYP2C19 by observing its recovering activity after inhibition. In a 5-phase study 10 healthy volunteers were administered 20 mg pantoprazole, 50 mg caffeine and 0.5 mg midazolam before and 1, 25, 49 and 73 hours after a 7 day pretreatment with 80mg esomeprazole twice daily. Esomeprazole increased the (R)-pantoprazole’s exposure up to 5-fold and the significant increase lasted at least 72 hours, which suggests strong MDI of CYP2C19. Esomeprazole had a minor effect on CYP3A4 and no effect on CYP1A2. The turnover half-life of CYP2C19 was estimated to be 46 hours. This estimation will be useful in the future for in vitro-in vivo extrapolations and physiologically based pharmacokinetic modeling of CYP2C19. Concomitant use of drugs metabolized by CYP2C19 should be considered cautiously because of the clinically relevant strong and prolonged inhibition of CYP2C19 by esomeprazole. Alterations in exposures to drugs metabolized by CYP2C19 are expected after discontinuation of esomeprazole treatment for at least 3-4 days.
  • Lilius, Tuomas O.; Blomqvist, Kim; Hauglund, Natalie; Liu, Guojun; Stæger, Frederik Filip; Bærentzen, Simone; Du, Ting; Ahlström, Fredrik; Backman, Janne T.; Kalso, Eija; Rauhala, Pekka V.; Nedergaard, Maiken (2019)
    Drug delivery to the central nervous system remains a major problem due to biological barriers. The blood-brainbarrier can be bypassed by administering drugs intrathecally directly to the cerebrospinal fluid (CSF). The glymphatic system, a network of perivascular spaces promoting fluid exchange between CSF and interstitial space, could be utilized to enhance convective drug delivery from the CSF to the parenchyma. Glymphatic flow is highest during sleep and anesthesia regimens that induce a slow-wave sleep-like state. Here, using mass spectrometry and fluorescent imaging techniques, we show that the clinically used alpha(2)-adrenergic agonist dexme-detomidine that enhances EEG slow-wave activity, increases brain and spinal cord drug exposure of intrathecally administered drugs in mice and rats. Using oxycodone, naloxone, and an IgG-sized antibody as relevant model drugs we demonstrate that modulation of glymphatic flow has a distinct impact on the distribution of intrathecally administered therapeutics. These findings can be exploited in the clinic to improve the efficacy and safety of intrathecally administered therapeutics.
  • Lehtisalo, Minna (Helsingin yliopisto, 2019)
    The xanthine oxidase inhibitor febuxostat was recently found to inhibit the breast cancer resistance protein (BCRP) in vitro. Rosuvastatin is a substrate of BCRP and genetic variability in BCRP markedly affects rosuvastatin pharmacokinetics. The aim of this study was to investigate possible effects of febuxostat and allopurinol, another xanthine oxidase inhibitor, on rosuvastatin pharmacokinetics. In a randomized, crossover study with three phases, 10 healthy volunteers ingested once daily placebo for 7 days, 300 mg allopurinol for 7 days, or placebo for 3 days followed by 120 mg febuxostat for 4 days, and a single 10 mg dose of rosuvastatin on day 6. Febuxostat increased the peak plasma rosuvastatin concentration 2.1-fold (90% confidence interval 1.8-2.6; P=5·10-5) and the area under the plasma rosuvastatin concentration-time curve 1.9-fold (1.5-2.5; P=0.001). Allopurinol, however, had no effect on rosuvastatin pharmacokinetics. These findings suggest that febuxostat inhibits BCRP-mediated rosuvastatin efflux in the small intestine. Concomitant use of febuxostat may increase the risk of rosuvastatin-induced muscle toxicity.
  • Tarkiainen, Katriina; Lehtisalo, Minna; Niemi, Mikko (2021)
    Lääkehoitoihin vaikuttavien geenien tutkiminen voi auttaa suunnittelemaan potilaalle sopivan lääkehoidon ja ehkäisemään lääkehoitojen haittavaikutuksia tai parantamaan hoidon tehoa.
  • Kokki, Hannu; Maaroos, Martin; Ellam, Sten; Halonen, Jari; Ojanpera, Ilkka; Ranta, Merja; Ranta, Veli-Pekka; Tolonen, Aleksandra; Lindberg, Oscar; Viitala, Matias; Hartikainen, Juha (2018)
    Purpose Cardiac surgery and conventional extracorporeal circulation (CECC) impair the bioavailability of drugs administered by mouth. It is not known whether miniaturized ECC (MECC) or off-pump surgery (OPCAB) affect the bioavailability in similar manner. We evaluated the metoprolol bioavailability in patients undergoing CABG surgery with CECC, MECC, or having OPCAB. Methods Thirty patients, ten in each group, aged 44-79 years, scheduled for CABG surgery were administered 50 mg metoprolol by mouth on the preoperative day at 8-10 a.m. and 8 p.m., 2 h before surgery, and thereafter daily at 8 a.m. and 8 p.m. Blood samples were collected up to 12 h after the morning dose on the preoperative day and on first and third postoperative days. Metoprolol concentration in plasma was analyzed using liquid chromatography-mass spectrometry. Results The absorption of metoprolol was markedly reduced on the first postoperative day in all three groups, but recovered to the preoperative level on the third postoperative day. The geometric means (90% confidence interval) of AUC(0-12) on the first and third postoperative days versus the preoperative day were 44 (26-74)% and 109 (86-139)% in the CECC-group, 28 (16-50)% and 79 (59-105)% in the MECC-group, and 26 (12-56)% and 96 (77-119)% in the OPCAB-group, respectively. Two patients in the CECC-group and two in the MECC-group developed atrial fibrillation (AF). The bioavailability and the drug concentrations of metoprolol in patients developing AF did not differ from those who remained in sinus rhythm. Conclusion The bioavailability of metoprolol by mouth was markedly reduced in the early phase after CABG with no difference between the CECC-, MECC-, and OPCAB-groups.
  • Kivikataja, Karla (Helsingin yliopisto, 2018)
    Petidiini ja oksikodoni ovat vahvoja kipulääkkeitä eli opioideja. Niitä käytetään synnytyskivun hoidossa pääasiassa synnytyksen alkuvaiheessa. Haittavaikutuksista yleisimpiä ovat pahoinvointi, huimaus, ummetus ja uneliaisuus. Suurin osa synnyttäjistä kokee synnytyskivun sietämättömänä tai voimakkaana. Kivun voimakkuutta voidaan kuvata VAS-janan (visual analogue scale) avulla. Siinä kivun voimakkuus merkitään 100 millimetriä pitkälle janalle, jonka toinen ääripää edustaa täysin kivutonta tilannetta (VAS 0 mm) ja toinen ääripää kovinta kuviteltavissa olevaa kipua (VAS 100 mm). Raskauden aikana tapahtuu monia fysiologisia muutoksia, jotka vaikuttavat systeemisten opioidien farmakokinetiikkaan. Tähän mennessä on tehty vain vähän tutkimuksia petidiinin ja oksikodonin vaikutusajasta raskaana olevilla naisilla. Tämän tutkimuksen avulla saadaan alustavaa lisätietoa siitä, kuinka lyhyillä annosväleillä näitä opioideja voidaan antaa synnytyksen alkuvaiheen kivunlievityksessä. Tutkimus tehtiin kyselylomakkeiden ja SPSS-analysointiohjelman avulla. Tutkimuksessa saatiin viitteitä siitä, että perinteisesti käytetyllä petidiinillä saattaa olla pidempi vaikutusaika kuin oksikodonilla. Tulosten perusteella on myös mahdollista, että VAS-lasku on suurempi oksikodonilla kuin petidiinillä. Lisäksi opioidien haittavaikutusprofiili näyttäisi olevan raskaana olevilla samankaltainen kuin muulla väestöllä. Pienen otoksen ja suurten keskihajontojen vuoksi suoria johtopäätöksiä näiden tutkimustulosten perusteella ei voida tehdä. Tulokset antavat kuitenkin arvokasta lisätietoa systeemisten opioidien käytöstä ensisynnyttäjillä. Samankaltaisia tutkimuksia tarvitaan lisää, jotta systeemisiä opioideja pystytään jatkossa käyttämään tällä potilasryhmällä mahdollisimman turvallisesti ja tehokkaasti.
  • Vahtera, Annukka; Valkonen, Miia; Huhtala, Heini; Pettila, Ville; Kuitunen, Anne (2017)
    Introduction: In intensive care unit (ICU) patients, subcutaneous low-molecular weight heparin thromboprophylaxis results in lower plasma anti-factor Xa (anti-FXa) levels compared to general ward patients. The aim of this study was to examine whether enoxaparin thromboprophylaxis given as a continuous intravenous infusion (CII) results in more constant and predictable anti-FXa concentration than standard subcutaneous bolus (SCB) administration. Materials and methods: This was a prospective, single-blind, multicenter, randomized controlled trial where ICU patients requiring thromboprophylaxis received enoxaparin either 40 mg as a SCB once daily or 40 mg as a CII over 24 h for three consecutive days. The primary outcome was maximum serum anti-FXa concentration (C-max24 (h)) within the first 24 h; the secondary outcome was anti-FXa area under the curve (AUC)((0-24 h)). Trough level was measured at 72 h. Results: Thirty-nine patients were included in the intention to treat analysis. The median anti-FXa C-max24 (h) was 0.05 (interquartile range, IQR, 0.05-0.18) IU/ml in the CII group and 0.18 (IQR, 0.12-0.33) IU/ml in the SCB group (p= 0.05). Median anti-FXa AUC((0-24 h)) was 1.20 (IQR, 0.98-2.88) in the CII and 1.54 (IQR, 1.22-4.12) in the SCB group (p = 0.095). After 72 h, 66.7% of patients in the CII group had a detectable anti-FXa concentration of > 0.1 IU/ml, compared with 16.7% in the SCB group (p = 0.019). Conclusions: Continuous infusion of enoxaparin led to lower anti-FXa C-max24 h than standard SCB administration. No difference in anti-FXa AUC(0-24) (h) was detected.
  • Bhattacharya, Madhushree; Sadeghi, Amir; Sarkhel, Sanjay; Hagström, Marja; Bahrpeyma, Sina; Toropainen, Elisa; Auriola, Seppo; Urtti, Arto (2020)
    Tissue barriers limit drug delivery in the eye. Therefore, retinal diseases are treated with intravitreal injections. Delivery systems with reduced dosing frequency and/or cellular drug delivery properties are needed. We present here a modular peptide-based delivery system for cell targeted release of dexamethasone in the retinal pigment epithelial cells. The peptide–dexamethasone conjugates consist of cell penetrating peptide, enzyme cleavable linker and dexamethasone that is conjugated with hydrazone bond. The conjugates are chemically stable in the vitreous, internalize into the retinal pigment epithelial cells and release dexamethasone intracellularly by en- zymatic action of cathepsin D. In vitro binding assay and molecular docking confirm binding of the released dexamethasone fragment to the human glucocorticoid receptor. In vivo rabbit studies show increased vitreal retention of dexamethasone with a peptide conjugate. Modular peptide conjugates are a promising approach for drug delivery into the retinal cells.
  • Katajavuori, Nina; Asikainen, Henna; Tengvall-Unadike, Unni; Kortejärvi, Hanna (2020)
    Objective: The aim of this study was to examine whether the flipped classroom method enhances the quality of students' learning by exploring the change in students' processes of understanding, their relation to study success, and students' experiences of the course. Methods: A mass pharmacokinetics course, comprising 148 second-year pharmacy students was transformed by using the flipped classroom method. Students answered a 'HowULearn' questionnaire in their first and last lecture before (n=126) and after the course (n=100) to measure their processes of understanding. Paired sample t-test, chi-square test and correlation analysis were used to analyse the change in students' scores, examine the relationship between the scales, and course grade. Students' experiences of the course were examined with open-ended questions, and these responses were analysed using qualitative content analysis. Results: The response rate to the first and second questionnaire was 68%. Surface-level processing statistically decreased significantly (t= 3.72; p Conclusions: The study showed that the flipped classroom approach resulted in decreased surface-level and increased deep-level processing. This suggests that the flipped classroom method can improve students' processes of understanding.
  • Fihlman, Mari; Hemmilä, Tuija; Hagelberg, Nora M.; Backman, Janne T.; Laitila, Jouko; Laine, Kari; Neuvonen, Pertti J.; Olkkola, Klaus T.; Saari, Teijo I. (2018)
    PurposeBuprenorphine has low oral bioavailability. Regardless of sublingual administration, a notable part of buprenorphine is exposed to extensive first-pass metabolism by the cytochrome P450 (CYP) 3A4. As drug interaction studies with buprenorphine are limited, we wanted to investigate the effect of voriconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics and pharmacodynamics of oral buprenorphine.MethodsTwelve healthy volunteers were given either placebo or voriconazole (orally, 400mg twice on day 1 and 200mg twice on days 2-5) for 5days in a randomized, cross-over study. On day 5, they ingested 0.2mg (3.6mg during placebo phase) oral buprenorphine. We measured plasma and urine concentrations of buprenorphine and norbuprenorphine and monitored their pharmacological effects. Pharmacokinetic parameters were normalized for a buprenorphine dose of 1.0mg.ResultsVoriconazole greatly increased the mean area under the plasma concentration-time curve (AUC(0-18)) of buprenorphine (4.3-fold, P
  • Fihlman, Mari; Hemmila, Tuija; Hagelberg, Nora M.; Kuusniemi, Kristiina; Backman, Janne T.; Laitila, Jouko; Laine, Kari; Neuvonen, Pertti J.; Olkkola, Klaus T.; Saari, Teijo I. (2016)
    This study aimed to determine possible effects of voriconazole and posaconazole on the pharmacokinetics and pharmacological effects of sublingual buprenorphine. We used a randomized, placebo-controlled crossover study design with 12 healthy male volunteers. Subjects were given a dose of 0.4 mg (0.6 mg during placebo phase) sublingual buprenorphine after a 5-day oral pretreatment with either (i) placebo, (ii) voriconazole 400 mg twice daily on the first day and 200 mg twice daily thereafter or (iii) posaconazole 400 mg twice daily. Plasma and urine concentrations of buprenorphine and its primary active metabolite norbuprenorphine were monitored over 18 h and pharmacological effects were measured. Compared to placebo, voriconazole increased the mean area under the plasma concentration-time curve (AUC(0-a)) of buprenorphine 1.80-fold (90 % confidence interval 1.45-2.24; P <0.001), its peak concentration (C-max) 1.37-fold (P <0.013) and half-life (t (A1/2) ) 1.37-fold (P <0.001). Posaconazole increased the AUC0(0-a) of buprenorphine 1.25-fold (P <0.001). Most of the plasma norbuprenorphine concentrations were below the limit of quantification (0.05 ng/ml). Voriconazole, unlike posaconazole, increased the urinary excretion of norbuprenorphine 1.58-fold (90 % confidence interval 1.18-2.12; P <0.001) but there was no quantifiable parent buprenorphine in urine. Plasma buprenorphine concentrations correlated with the pharmacological effects, but the effects did not differ significantly between the phases. Voriconazole, and to a minor extent posaconazole, increase plasma exposure to sublingual buprenorphine, probably via inhibition of cytochrome P450 3 A and/or P-glycoprotein. Care should be exercised in the combined use of buprenorphine with triazole antimycotics, particularly with voriconazole, because their interaction can be of clinical importance.