Using positron emission tomography imaging, we determined the hepatic concentrations and hepatobiliary transport of [11C]rosuvastatin (RSV; i.v. injection) in the absence (n = 6) and presence (n = 4 of 6) of cyclosporin A (CsA; i.v. infusion) following a therapeutic dose of unlabeled RSV (5 mg, p.o.) in healthy human volunteers. The sinusoidal uptake, sinusoidal efflux, and biliary efflux clearance (CL; mL/minute) of [11C]RSV, estimated through compartment modeling were 1,205.6 ± 384.8, 16.2 ± 11.2, and 5.1 ± 1.8, respectively (n = 6). CsA (blood concentration: 2.77 ± 0.24 μM), an organic‐anion‐transporting polypeptide, Na+‐taurocholate cotransporting polypeptide, and breast cancer resistance protein inhibitor increased [11C]RSV systemic blood exposure (45%; P < 0.05), reduced its biliary efflux CL (52%; P < 0.05) and hepatic uptake (25%; P > 0.05) but did not affect its distribution into the kidneys. CsA increased plasma concentrations of coproporphyrin I and III and total bilirubin by 297 ± 69%, 384 ± 102%, and 81 ± 39%, respectively (P < 0.05). These data can be used in the future to verify predictions of hepatic concentrations and hepatobiliary transport of RSV.

We determined whether in vivo transporter-mediated hepatobiliary clearance (CL) and hepatic concentrations of rosuvastatin (RSV) in the rat could be predicted by transport activity in sandwich-cultured rat hepatocytes (SCRHs) and/or transporter-expressing cell lines scaled by differences in transporter protein expression between SCRHs, cell lines, and rat liver. The predicted hepatobiliary CLs and hepatic concentrations of RSV were compared with our previously published positron emission tomography imaging data. Sinusoidal uptake CL ([Formula: see text] [Formula: see text] [Formula: see text] [Formula: see text] [Formula: see text] [Formula: see text] for Oatp protein expression. This is the first demonstration of the successful prediction of in vivo hepatobiliary CLs and hepatic concentrations of RSV using transporter-expressing cells and SCRHs.

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The aim of the present study was to investigate the mechanism for the stereoselective presystemic clearance of carvedilol. We examined the oxidation and glucuronidation of carvedilol in human liver microsomes (HLM) and human intestinal microsomes (HIM). The oxidation of carvedilol in HLM and HIM was evaluated in the presence of NADPH, whereas glucuronidation was evaluated in the presence of UDP-glucuronic acid. Oxidation of S-carvedilol in HLM and HIM was greater than that of R-carvedilol. In addition, the oxidation of R-carvedilol in HLM was inhibited by quinidine, whereas that of S-carvedilol was inhibited by both quinidine and furafylline. On the other hand, R-and S-carvedilol oxidation in HIM was inhibited by ketoconazole. Glucuronidation of Scarvedilol in HLM and HIM was also higher than that of R-carvedilol. These results suggested that cytochrome P450 (CYP) 2D6 and CYP1A2 are involved in the stereoselective oxidation of carvedilol in the liver, that CYP3A4 is involved in intestinal oxidation, and that glucuronidation in the liver and intestine is at least partly responsible for stereoselective presystemic clearance.

No abstract

Quinidine, a tertiary amine compound with a site of ionization with a pK a value of pH 8.8, is classified as a type IA antiarrhythmic drug, and has been used for the management of ventricular arrhythmias.1,2) The drug is absorbed rapidly and almost entirely after oral administration, and is detected in the plasma within 15 min.3) Quinidine binds to both albumin and a 1 -acid glycoprotein, and the proportion that binds to plasma protein is 70 to 95%. 4) However, its apparent volume of distribution is quite large (2.0 to 3.5 liters/kg), because the drug is highly lipophilic.4) It is metabolized via 3-hydroxylation and N-oxygenation by cytochrome P450 3A4, and these metabolites are less electrophysiologically active than the parent drug. 5,6) The hepatic extraction ratio of quinidine is about 30%, and the bioavailability after oral administration is about 70%. 7) In addition, quinidine is partly excreted in the urine (15 to 40% of dose), suggesting that reabsorption at the distal tubules in the nephron is not complete. 4)The mechanism of intestinal absorption of lipophilic organic cations has been explained as passive diffusion of unionized compounds according to the pH-partition theory. On the other hand, Mizuuchi et al. investigated the mechanisms responsible for the transcellular transport of diphenhydramine in Caco-2 cells. 8,9) This cell line forms confluent monolayers of well differentiated enterocyte-like cells with functional properties of transporting epithelia, and is widely used as a model to study the absorption of drugs and other xenobiotics.10-12) The uptake of diphenhydramine at the apical membrane in Caco-2 cells was pH-and temperature-dependent, but was not inhibited by tetraethylammonium, biological amines, or neurotransmitters.8) On the other hand, the uptake was inhibited by chlorpheniramine, procainamide, and imipramine, and was trans-stimulated by the preloading of chlorpheniramine, dimethylaminochloride, and triethylamine.8,9) From these results, Mizuuchi et al. concluded that the uptake of diphenhydramine at the apical membrane in Caco-2 cells is mediated by a specific transport system, and that this system recognizes the N-dimethyl or N-diethyl moieties of compounds. 8,9) However, at present, it is unclear whether the transport system for diphenhydramine is involved in the intestinal absorption of other tertiary amine compounds, such as quinidine.During drug absorption in the intestine, therapeutic compounds or nutrients first enter intestinal epithelial cells from their apical side, then pass through the epithelia to the basolateral side, and finally appear in the blood stream. Therefore, to investigate intestinal drug absorption, it is important to separately assess these sequential processes. However, in many cases, drug transport on the apical and basolateral sides of the monolayer in Caco-2 cells was not separately examined, and the influx and efflux clearance rates were not evaluated.13) For the characterization of transcellular drug transport, a pharmacokinetic approach is useful. Tr...

The intestinal expression of the CYP3A subfamily was investigated in female rats, and the intestinal metabolism of two CYP3A substrates, testosterone and rifabutin, was examined and compared between males and females. CYP3A1/23 and CYP3A2 intestinal expression was barely detected in male and female rats. Although CYP3A9 was predominantly expressed in the female rat liver, its expression in the intestine was not different between the two sexes. The rate of testosterone 6b b-hydroxylation in the female intestine was similar to that for males. Rifabutin was also metabolized at similar rates in both intestines, although the metabolic rate was greater in the female liver. These results indicate that the intestinal drug metabolizing activity of the CYP3A subfamily is similar between males and females, and that CYP3A9 is involved in the intestinal metabolism of CYP3A substrates in both sexes.

To characterize the intestinal absorption of digoxin, its transcellular transport and drug interaction activity was investigated using Caco-2 cell monolayers. We examined digoxin transport in the presence and absence of ouabain to determine whether digoxin binding to Na ؉ ,K ؉ -ATPase affects its transcellular digoxin transport, and evaluated its influx and efflux clearance by model-dependent pharmacokinetic analysis. Transcellular transport in the basal-to-apical direction was greater than that in the opposite direction. In addition, ouabain decreased the cellular accumulation of digoxin, but it did not alter its transcellular transport profile. The observations for transcellular transport and cellular accumulation in the presence of ouabain were used for the pharmacokinetic analysis, which showed that the efflux clearance of digoxin on the apical side of the monolayer was 15 times greater than that on the basal side. Apical-to-basal transport was increased by carvedilol and pimobendan, and these compounds suppressed the efflux clearance on the apical side and the influx clearance on the basal side. These findings indicate that the intestinal absorption of digoxin is primarily dominated by the efflux process on the luminal side of the intestine, and that carvedilol and pimobendan may vary the rate of intestinal digoxin absorption mainly by inhibiting its exsorptive transport.