Mitoquinone (MitoQ₁₀ mesylate) is a mitochondria-targeted antioxidant for the treatment of neurodegenerative diseases. As the oral bioavailability of mitoquinone is low in rat, it is necessary to better understand the mechanisms of its absorption in rat and in human. The aims of this thesis were 1) to investigate oral absorption mechanisms of mitoquinone in Caco-2 cell monolayers and in a rat intestinal tissue model; 2) to investigate the correlation between chemical structure and permeability of mitoquinone analogues in Caco-2 cell monolayers; and 3) to explore the hypothesis that active transport and/or drug metabolism contribute to the pharmacokinetics of oral mitoquinone in rat.
In Caco-2 studies, transport of mitoquinone was polarized with the apparent permeability (P[app]) from basolateral (BL) to apical (AP) (P[appBL to AP]) being >2.5-fold the P[app] from AP to BL (P[appAP to BL]). The P[appBL to AP] value decreased by 26%, 31% and 61% by P-glycoprotein (P-gp) inhibitors verapamil 100 [mu]M, cyclosporine A (CsA) 10 [mu]M and CsA 30 [mu]M, respectively, whereas the P[appAP to BL] increased 71% by CsA 30 [mu]M. Some of the intracellular mitoquinone was reduced to mitoquinol and subsequently metabolized to glucuronide and sulfate conjugates. Apical effluxes of mitoquinol sulfate and mitoquinol glucuronide conjugates were significantly decreased by cyclosporine A 30 [mu]M and the breast cancer receptor protein (BCRP) inhibitor, reserpine 25 [mu]M, respectively. In the presence of 4% bovine serum albumin on the BL side, the P[appAP to BL] was 4.52 � 0.92 x 10⁶ cm/s. Based on a absorption-disposition model, F[a] value of mitoquinone in human is estimated to be 56%.
A bellshaped relationship exists between the Caco-2 permeability of mitoquinone analogues and their lipophilicity. Permeability of mitoquinone analogues initially increases as lipophilicity increase, reaches a maximum, and then decreases due to significant cellular accumulation and active efflux. The physicochemical parameters of mitoquinone and its analogues (such as log P or polar surface area) alone do not predict their permeability across the cell membranes.
The bidirectional transport of mitoquinone displays polarity across rat ileal mucosa. The P[app] from s to m (P[app s to m) of mitoquinone decreased and P[app m to s] increased but not significantly by P-gp inhibitor CsA 30 [mu]M. The tissue accumulation of mitoquinone was ~16% of the total amount of mitoquinone added. In addition, several phase I and one phase II metabolites generated by rat ileum tissue were detected.
Results from pharmacokinetic studies indicate that mitoquinone was poorly (~24%) but rapidly absorbed and conjugated after oral administration. It was quickly excreted as unchanged drug and as its glucuronides (the major metabolites in rat) into intestine where it was reabsorbed. P-gp inhibition studies in rat indicate that inhibition of P-gp may increase the intestinal absorption of mitoquinone, but cannot change its oral bioavailability due to increased first-pass phase II metabolism and decreased enterohepatic recycling.
In conclusion, mitoquinone is poorly absorbed in rat but may be well absorbed in human. The barrier functions of intracellular metabolism and the action of P-gp to oral absorption of mitoquinone in human may be less significant, whereas P-gp play an important role in the absorption and disposition of mitoquinone in rat in vivo. These results, together with those from its analogues, demonstrate that the actual absorption profile of a compound depends on its intrinsic membrane permeability, transporter affinity, metabolizing enzyme affinity and plasma protein binding affinity.
| Identifer | oai:union.ndltd.org:ADTP/217732 |
| Date | January 2007 |
| Creators | Li, Yan, n/a |
| Publisher | University of Otago. School of Pharmacy |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://policy01.otago.ac.nz/policies/FMPro?-db=policies.fm&-format=viewpolicy.html&-lay=viewpolicy&-sortfield=Title&Type=Academic&-recid=33025&-find), Copyright Yan Li |
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