Involvement of influx and efflux transport systems in gastrointestinal absorption of celiprolol

Kato, Yukio; Miyazaki, T.; Kano, Takashi; Sugiura, Tomoko; Kubo, Yoshiyuki; Tsuji, Akira

doi:10.1002/jps.21618

Cited by 65 publications

(61 citation statements)

References 37 publications

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“…The search was extended to other sources for biliarily eliminated drugs (44)(45)(46)(47)(48)(49)(50)(51). Drugs were considered nonsubstrates for efflux ratios<1.8 and substrates if the efflux ratio was>2.2.…”

Section: Additional Considerationsmentioning

confidence: 99%

Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

Hosey-Cojocari

Broccatelli

Benet

2014

AAPS J

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Abstract. Biliary excretion is an important route of elimination for many drugs, yet measuring the extent of biliary elimination is difficult, invasive, and variable. Biliary elimination has been quantified for few drugs with a limited number of subjects, who are often diseased patients. An accurate prediction of which drugs or new molecular entities are significantly eliminated in the bile may predict potential drug-drug interactions, pharmacokinetics, and toxicities. The Biopharmaceutics Drug Disposition Classification System (BDDCS) characterizes significant routes of drug elimination, identifies potential transporter effects, and is useful in understanding drug-drug interactions. Class 1 and 2 drugs are primarily eliminated in humans via metabolism and will not exhibit significant biliary excretion of parent compound. In contrast, class 3 and 4 drugs are primarily excreted unchanged in the urine or bile. Here, we characterize the significant elimination route of 105 orally administered class 3 and 4 drugs. We introduce and validate a novel model, predicting significant biliary elimination using a simple classification scheme. The model is accurate for 83% of 30 drugs collected after model development. The model corroborates the observation that biliarily eliminated drugs have high molecular weights, while demonstrating the necessity of considering route of administration and extent of metabolism when predicting biliary excretion. Interestingly, a predictor of potential metabolism significantly improves predictions of major elimination routes of poorly metabolized drugs. This model successfully predicts the major elimination route for poorly permeable/poorly metabolized drugs and may be applied prior to human dosing.

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Section: Additional Considerationsmentioning

confidence: 99%

Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

Hosey-Cojocari

Broccatelli

Benet

2014

AAPS J

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“…A previous study has proposed that several b-blockers are OATP1A2 substrates (Kato et al, 2009). Initially, their study aimed at determining the transporters involved in the gastrointestinal absorption of celiprolol to understand the fooddrug interaction induced by citrus juices using an animal model.…”

Section: Introductionmentioning

confidence: 99%

Effects of β-Blockers and Tricyclic Antidepressants on the Activity of Human Organic Anion Transporting Polypeptide 1A2 (OATP1A2)

Michaud

Moya

et al. 2015

J Pharmacol Exp Ther

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The organic anion transporting polypeptide 1A2 (OATP1A2), a membrane drug transporter expressed on important organs (such as the brain, kidney, and intestine) may be a key element in the disposition of drugs. Previous studies demonstrated that it could transport a broad spectrum of substrates, including endogenous molecules and clinically relevant drugs, such as several b-blockers and 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors. The primary objective of this study was to investigate OATP1A2 transport activity using rosuvastatin as a probe substrate and evaluate competitive inhibition of its transport by b-blockers. Rosuvastatin transport was saturable, with a K m of 60.2 mM. With the exception of carvedilol (IC 50 of 3.2 mM), all of the other b-blockers that were evaluated had a small or insignificant effect on OATP1A2-mediated uptake of rosuvastatin. Carvedilol differs from the other b-blockers by the tricyclic moiety in its chemical structure. As a secondary objective, the transport of a series of tricyclic compounds by OATP1A2 and their potential for rosuvastatin transport inhibition were evaluated. Tricyclic compounds were not OATP1A2 substrates. On the other hand, tricyclic compounds with a short aliphatic amine chain inhibited OATP1A2-mediated rosuvastatin transport. Our data suggest that these drugs may modulate the transport of OATP1A2 substrates and may affect drug actions.

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“…15) In addition, a decreased intraduodenal pH induced by grapefruit juice could lead to reduced absorption of celiprolol because the nonionized form is more lipid-soluble (and thus better absorbed) than the ionized form. Therefore, possible involvement of other factors such as P-glycoprotein-mediated efflux transport and a physicochemical factor, in the drug interaction shown in this study cannot be ruled out.…”

Section: Discussionmentioning

confidence: 99%

“…11,15,16) In clinical settings, it is important to know how long OATP inhibition will be sustained after the intake of grapefruit juice, so that practitioners can administer drugs without the concern of interactions. Several reports have been published about the duration of CYP3A4 inhibition.…”

Section: )mentioning

confidence: 99%

“…10) Furthermore, celiprolol, a β-adrenoceptor blocking agent, has been reported to be a substrate of uptake transporters such as OATP1A2 and OATP2B1, and markedly reduced drug absorption when co-administered with grapefruit juice. 11,15,16) In clinical settings, it is important to know how long OATP inhibition will be sustained after the intake of grapefruit juice, so that practitioners can administer drugs without the concern of interactions. Several reports have been published about the duration of CYP3A4 inhibition.…”

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confidence: 99%

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Comparison of Inhibitory Duration of Grapefruit Juice on Organic Anion-Transporting Polypeptide and Cytochrome P450 3A4

Tanaka

Uchida

Miyakawa

et al. 2013

Biological & Pharmaceutical Bulletin

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Recently, a new type of interaction has been reported in which fruit juices diminish oral drug bioavailability through inhibition of organic anion-transporting polypeptide (OATP). In this study, we aimed to clarify the duration of OATP inhibition by grapefruit juice (GFJ), and to compare it with the duration of GFJ-induced inhibition of cytochrome P450 (CYP) 3A4 activity. Seven healthy volunteers were enrolled in this open-label, single-sequence study. They were orally administered celiprolol (100 mg) and midazolam (15 µg/kg) with water on the control day. Three days later, they ingested GFJ (200 mL) 3 times a day for 3 d. On day 1, the same drugs were administered with GFJ. On days 3 and 7, the same drugs were administered with water. Pharmacokinetics of both drugs were evaluated on each trial day. The peak plasma concentration (C max ) and the area under the plasma concentration-time curve from 0 to 8 h (AUC 0-8 ) of celiprolol significantly decreased on day 1, and the mean ratios of these values and the corresponding control-day values were 0.18 and 0.25, respectively. The C max and AUC 0-8 returned to the control levels on days 3 and 7. In contrast, AUC 0-8 of midazolam were higher on days 1 and 3 than on the control day (mean ratio, 2.12 and 1.47, respectively). The AUC 0-8 returned to the control level on day 7. In conclusion, results of this study indicated that the OATP inhibition caused by GFJ dissipated faster than GFJ-mediated alterations in CYP3A4 activity, which were sustained for at least 48 h.Key words organic anion-transporting polypeptide; cytochrome P450; grapefruit juice Food and medication are often taken together. However, certain foods interact with drugs by altering mechanisms that are important determinants of systemic drug availability. In particular, grapefruit juice is known to alter the pharmacokinetics of over 30 prescription drugs by affecting their bioavailability.1-3) The mechanism of this interaction is inhibition of intestinal cytochrome P450 (CYP) 3A4 activity and increased systemic exposure of CYP3A4 substrates. [4][5][6][7][8] In 2012, the United States Food and Drug Administration issued a press release to warn consumers that the intake of grapefruit juice along with medication could cause dangerous side effects. 9)Recently, a new type of interaction has been reported in which fruit juices diminish oral drug bioavailability through inhibition of the organic anion-transporting polypeptide (OATP) uptake transporter, which is a family of membrane solute carrier (SLC) transporters. OATP influences the intestinal absorption of several drugs in clinical use. [10][11][12][13][14] Grapefruit juice decreases the plasma concentrations of some drugs including β-adrenoceptor blocking agents and antihistamines by this mechanism. For example, grapefruit juice was reported to reduce the area under the plasma concentration-time curve (AUC) value for fexofenadine to a mean value of 58% of that when the drug was administered with the corresponding volume of water.10) Furthermore, celiprolol, ...

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Involvement of influx and efflux transport systems in gastrointestinal absorption of celiprolol

Cited by 65 publications

References 37 publications

Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

Effects of β-Blockers and Tricyclic Antidepressants on the Activity of Human Organic Anion Transporting Polypeptide 1A2 (OATP1A2)

Comparison of Inhibitory Duration of Grapefruit Juice on Organic Anion-Transporting Polypeptide and Cytochrome P450 3A4

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