Browsing by discipline "Klinisk farmakologi och läkemedelsbehandling"

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.

Several protein kinase inhibitors are known to be mechanism-based inhibitors of cytochrome P450 (CYP) enzymes, especially CYP3A4. Mechanism-based inhibition of CYP enzymes by a drug may have long lasting and serious consequences due to the irreversible nature of the inhibition. The CYP enzyme must be resynthesized before regaining functionality, affecting the concentrations of other drugs metabolized by the same CYP enzymes and potentially leading to drug-drug interactions. Six protein kinase inhibitors were tested for mechanism-based inhibition of CYP2C8 and CYP3A4 using human liver microsomes; masitinib, midostaurin, nintedanib, quizartinib, trametinib and vatalanib. Amodiaquine was used as the substrate for CYP2C8, while midazolam was the CYP3A4 substrate. None of the inhibitors tested displayed time-dependent inhibition of CYP2C8. Midostaurin and nintedanib exhibited time-dependent inhibition of CYP3A4 while masitinib, quizartinib, trametinib and vatalanib did not. Both midostaurin and nintedanib had an inhibitor concentration causing a 50% inhibition (IC50) shift of >1.5-fold with increased inhibition of CYP3A4 after preincubation with NADPH for 30 minutes when compared to no preincubation. The mechanism-based inactivation constants kinact (the maximal inactivation rate) and KI (the inhibitor concentration that supports half-maximal rate of inactivation) were determined for midostaurin and nintedanib. The kinact values were 0.053 1/min for midostaurin and 0.024 1/min for nintedanib, while the KI values were 2.65 µM for midostaurin and 16.5 µM for nintedanib. Predictions using a mechanistic static model suggested that nintedanib is unlikely to cause CYP3A4 mediated drug-drug interactions, while midostaurin was predicted to increase the exposure of CYP3A4 substrates by several times. Reversible inhibition by trametinib is unlikely to cause drug-drug interactions involving either CYP2C8 or CYP3A4 substrates. On the other hand, masitinib and vatalanib were predicted to increase the exposure of CYP2C8 and CYP3A4 substrates several fold. In conclusion, two protein kinase inhibiters were identified as mechanism-based inhibitors of CYP3A. Mechanism-based inhibition of CYP enzymes by protein kinase inhibitors has the potential to cause severe long lasting consequences and careful testing should be conducted to determine the actual clinical drug-drug interaction risk.

Tutkimuksen tavoitteena oli selvittää, miten Streptococcus salivarius M18 – kantaa (1 x 109 c.f.u), Lactobacillus rhamnosus GG (1 x 109 c.f.u) ja ksylitolia (0,5 g) sisältävä apteekissa myytävä probiottinen pureskeluvalmiste vaikuttaa Streptococcus mutansin määrään 9-10 –vuotiailla lapsilla. Tutkimusryhmän lapset (n=22) kerättiin kahdesta Helsingin alakoulusta eikä terveydellisiä poissulkukriteerejä ollut. Valmistetta käytettiin hampaiden pesun jälkeen aamulla ja illalla 30 vuorokauden ajan. Valmistavaa suun desinfektiota ei tehty. Verrokkiryhmän lapset (n=16) olivat tutkimusryhmän rinnakkaisluokalla ja he eivät käyttäneet tuotetta. Sylkinäytteet kerättiin samanaikaisesti molemmilta ryhmiltä. Ryhmien sylkinäytteistä analysoitiin virtaussytometrian avulla S. mutansin ja S. salivariuksen prosenttiosuudet kokonaisbakteerimäärästä. Tutkimuksessa havaittiin, että valmistetta käyttäneillä lapsilla S. mutansin määrä väheni tilastollisesti merkitsevästi verrokkiryhmän lapsiin verrattuna. S. mutansin määrän vähenemistä saattaa selittää S. salivarius M18 – kannan antimikrobiset ominaisuudet, L. rhamnosus GG:n vaikutus tai tutkimuksen aikana kohentunut suuhygienia. Täysin varmoja johtopäätöksiä siitä, mikä oli S.mutansin määrän vähenemisen syynä, ei voida tässä tutkimuksessa tehdä, vaan laajempia tutkimuksia suositellaan.