1. Doxorubicin exhibited dose-independent pharmacokinetics after intravenous (5-20 mg/kg) and oral (20-100 mg/kg) administration to rats. Nearly all (82.1-99.7%) of the orally administered doxorubicin remained unabsorbed, and the hepatic first-pass extraction ratio and oral bioavailability of doxorubicin were approximately 0.5% and 1%, respectively. Based on these results, it is likely that the primary factor responsible for the low oral bioavailability of doxorubicin is the limited intestinal absorption, rather than the CYP3A4-mediated first-pass metabolism. 2. Moreover, the in vitro transport and cellular uptake studies using Caco-2 cell monolayers have revealed that doxorubicin crosses the intestinal epithelium primarily via the paracellular pathway (accounting for 85.6% of the overall absorptive transport) probably due to its physicochemical properties (hydrophilic cation; pKa = 9.67, log P = -0.5). These results suggest that P-glycoprotein (P-gp)-mediated efflux activity does not play a significant role in limiting the intestinal absorption of doxorubicin, attenuating the absorptive transport by only 5.56-13.2%. 3. Taken together, the present study demonstrated that the limited and paracellular intestinal absorption of doxorubicin was a major factor responsible for its low oral bioavailability, restricting the role of CYP3A4-mediated first-pass metabolism and P-gp-mediated efflux.

No abstract

In [Towards invariants of surfaces in 4-space via classical link invariants, Trans. Amer. Math. Soc.361 (2009) 237–265], Lee defined a polynomial [[D]] for marked graph diagrams D of surface-links in 4-space by using a state-sum model involving a given classical link invariant. In this paper, we deal with some obstructions to obtain an invariant for surface-links represented by marked graph diagrams D by using the polynomial [[D]] and introduce an ideal coset invariant for surface-links, which is defined to be the coset of the polynomial [[D]] in a quotient ring of a certain polynomial ring modulo some ideal and represented by a unique normal form, i.e. a unique representative for the coset of [[D]] that can be calculated from [[D]] with the help of a Gröbner basis package on computer.

Oral administration remains the preferred dosing method in clinical practice and drug development. Oral bioavailability (F) is a function of the fraction absorbed (Fabs), gastrointestinal or gut wall availability (FG), and hepatic availability (FH). Therefore, predicting intestinal absorption (Fabs) and first-pass elimination (FG and FH) from in vitro data may facilitate the selection of more orally bioavailable drug candidates in earlier stages of drug discovery and development. This review provides an overview of the determinants of intestinal absorption and first-pass elimination of drugs and focuses on the principles and applications of conventional in vitro--in vivo extrapolation (IVIVE) methods to predict Fabs, FG, and FH in humans.

A marked graph diagram is a link diagram possibly with marked 4-valent vertices. S. J. Lomonaco, Jr. and K. Yoshikawa introduced a method of representing surface-links by marked graph diagrams. Specially, K. Yoshikawa suggested local moves on marked graph diagrams, nowadays called Yoshikawa moves. It is now known that two marked graph diagrams representing equivalent surface-links are related by a finite sequence of these Yoshikawa moves. In this paper, we provide some generating sets of Yoshikawa moves on marked graph diagrams representing unoriented surface-links, and also oriented surfacelinks. We also discuss independence of certain Yoshikawa moves from the other moves.Mathematics Subject Classification 2000: 57Q45; 57M25.

No abstract

Carrell defined the fundamental biquandle of an oriented surface-link by a presentation obtained from its broken surface diagram, which is an invariant up to isomorphism of the fundamental biquandle. Ashihara gave a method to calculate the fundamental biquandle of an oriented surface-link from its marked graph diagram (ch-diagram). In this paper, we discuss the fundamental Alexander biquandles of oriented surface-links via marked graph diagrams, derived computable invariants and their applications to detect non-invertible oriented surface-links.

No abstract