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Buggins, Talia Rae
Languages: English
Types: Doctoral thesis
Subjects: RM
This thesis investigates the potential of some commonly used pharmaceutical excipients to alter drug pharmacokinetics. In breath test studies, 3.2ml/kg DMSO prolonged the half-life of 14C-aminopyrine, -erythromycin and -NDMA, indicating in vivo inhibition of metabolism by CYP3A (erythromycin), CYP2E1 (NDMA) and the variety of enzymes that metabolise aminopyrine (CYP 2C11, 2C12, 2B1 and 2B2). However, no effects were apparent at doses typically used in pre-clinical formulations. Aminopyrine and erythromycin breath tests were not affected by propylene glycol (PG) or Solutol HS15, however PG did significantly increase 14C02 exhalation half- life in the NDMA breath test, suggesting a specific effect on metabolism by CYP2E1. While two 2ml/kg doses of DMSO increased plasma ai-AGP levels, none of the excipients tested consistently affected plasma ai-AGP at doses commonly used in pre-clinical formulations, suggesting that they are unlikely to increase protein binding by this mechanism. Transport studies in MDCK-MDR1 cells demonstrated an inhibitory effect of 0.1% Tween 80 and Solutol HS15 on P-Gp. In vivo, Tween inhibited the biliary elimination of 99mTc-MIBI but not 99mTc-HIDA, indicating inhibition of P-Gp, while Solutol inhibited the biliary elimination of both radiopharmaceuticals, suggesting inhibition of MRP and possibly P-Gp. Pre-treatment with 4ml/kg DMSO substantially impaired the renal elimination of 99mTc-DTPA. In contrast, 20% 1.8ml/kg DMSO significantly increased 99mTc-DTPA uptake into the kidneys, suggesting an increase in GFR. Both Tween and Solutol delayed 99mTc-DTPA elimination from the kidneys in some rats, without affecting GFR. However, Solutol did not significantly affect the pharmacokinetics of OAT or OCT substrates, suggesting it did not affect active renal secretion by these transporters. These results demonstrate that excipients can influence drug pharmacokinetics in vivo, after a single acute dose at levels commonly used in pre clinical studies.
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