Variability of Bioavailability and Intestinal Absorption Characteristics of Bisoprolol

Abstract

We previously reported that renal function is partly responsible for the interindividual variability of the pharmacokinetics of bisoprolol. The aim of the present study was to examine the variability of bioavailability (F) of bisoprolol in routinely treated Japanese patients and intestinal absorption characteristics of the drug. We first analyzed the plasma concentration data of bisoprolol in 52 Japanese patients using a nonlinear mixed effects model. We also investigated the cellular uptake of bisoprolol using human intestinal epithelial LS180 cells. The oral clearance (CL/F) of bisoprolol in Japanese patients was positively correlated with the apparent volume of distribution (V/F), implying variable F. The uptake of bisoprolol in LS180 cells was temperature-dependent and saturable, and was significantly decreased in the presence of quinidine and diphenhydramine. In addition, the cellular uptake of bisoprolol dissolved in an acidic buffer was markedly less than that dissolved in a neutral buffer. These findings suggest that the rate/extent of the intestinal absorption of bisoprolol is another cause of the interindividual variability of the pharmacokinetics, and that the uptake of bisoprolol in intestinal epithelial cells is highly pH-dependent and also variable.

Importance of Lipophilicity and Polar Surface Area of Compounds on the Transport Activity of Intestinal H⁺/tertiary Amine Antiporter

“…On the other hand, the uptake of quinidine was decreased by Acute-NH4Cl treatment, which induces the alkalization of intracellular pH (Fig 1A). 4,5) The pro le of intracellular pH-dependent uptake of quinidine into HT-29 cells was also consistent with that in Caco-2 and LS180 cells (Fig 1). These ndings suggested that the H + antiporter(s) in HT-29 cells may be similar/identical to that (those) in Caco-2 and LS180 cells.…”

“…In addition, the uptake of quinidine into Caco-2, LS180, and HT-29 cells was significantly inhibited by diphenhydramine (Fig 1). Furthermore, Pre-NH4Cl treatment, which induces the acidification of intracellular pH, 4,5) increased the uptake of quinidine into HT-29 cells (Fig 1A). On the other hand, the uptake of quinidine was decreased by Acute-NH4Cl treatment, which induces the alkalization of intracellular pH (Fig 1A).…”

“…[3][4][5][6] Furthermore, other research groups reported that the postulated H + /tertiary amine antiporter can transport clonidine, 3,4-methylendioxymethanphetamine, phenylethylamine, and so on. [7][8][9] That is, many cat- …”

Pharmacokinetic variability of flecainide in younger Japanese patients and mechanisms for renal excretion and intestinal absorption

“…Our previous study suggested that the rate/extent of the intestinal absorption of bisoprolol is one of the causes of the interindividual variability of the pharmacokinetics of the drug [14]. In addition, the cellular uptake of bisoprolol into intestinal epithelial cells is plausibly mediated by the postulated H + /tertiary amine antiporter [14]. In the present study, the cellular uptake of flecainide in LS180 cells was significantly decreased by acidification of the extracellular medium, and was inhibited by tertiary amines, such as diphenhydramine and quinidine (Figure 4, Table 3).…”

“…To evaluate the cellular uptake of flecainide, the LS180 cells were seeded on plastic dishes of a multiwell plate as described previously . The composition of the incubation medium was as follows: 125 m m NaCl, 4.8 m m KCl, 5.6 m m d ‐glucose, 1.2 m m CaCl 2 , 1.2 m m KH 2 PO 4 , 1.2 m m MgSO 4 · 7H 2 O and 25 m m 2‐[4‐(2‐hydroxyethyl)‐1‐piperazyl]ethanesulfonic acid (HEPES) (pH 6.4 or 7.4).…”