Transport characteristics of candesartan in human intestinal Caco‐2 cell line

Zhou, Lei; Chen, Xiaoping; Gu, Yuanqing; Liang, Jin-Yu

doi:10.1002/bdd.664

Cited by 25 publications

(11 citation statements)

References 16 publications

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“…In addition, P-glycoprotein (P-gp) is well known to play a significant role in drug absorption from the gastrointestinal lumen, indicating the modulation of P-gp can mediate drug–drug interactions. 18 Candesartan is reported as a P-gp substrate, 19 but amlodipine might be devoid of P-gp inhibiting properties. 20 Therefore, significant pharmacokinetic alterations both in amlodipine by candesartan and in candesartan by amlodipine are unlikely.…”

Section: Discussionmentioning

confidence: 99%

No pharmacokinetic interactions between candesartan and amlodipine following multiple oral administrations in healthy subjects

Kim¹,

Kim²,

Huh³

et al. 2018

DDDT

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PurposeTo evaluate the pharmacokinetics and pharmacodynamics of candesartan and amlodipine in the absence and presence of each other in healthy subjects.MethodsThis study consisted of two parts: part 1, the effect of amlodipine on candesartan; part 2, the effect of candesartan on amlodipine. Each part was designed as a randomized, open-label, two-sequence, two-period, two-intervention crossover study with 20 subjects and performed separately in different populations. Pharmacokinetic assessments were performed over 48 hours for candesartan in part 1 and 72 hours for amlodipine in part 2 after drug administration on Day 10. Safety data included the results of physical examinations, clinical laboratory tests, vital signs, an electrocardiogram, and adverse events.ResultsFor both candesartan and amlodipine, the 90% confidence intervals for the geometric mean ratios of area under the concentration-time curve from time zero to the time of dosing interval of 24 hours and maximum concentration after drug administration fell within the bioequivalence acceptance criteria. Although this study was conducted in normotensive subjects, blood pressure lowering effects were observed in all intervention groups and co-administration of candesartan and amlodipine reduced blood pressure more than amlodipine alone, but similar to candesartan alone. No serious adverse event was reported throughout the study, and all treatment emergent adverse events were mild to moderate in severity and were recovered without sequelae.ConclusionCo-administration of candesartan and amlodipine did not change the systemic exposure of each drug alone in healthy subjects. The administration of candesartan 32 mg alone, amlodipine 10 mg alone, and co-administration of candesartan and amlodipine were well tolerated during the study.

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Section: Discussionmentioning

confidence: 99%

No pharmacokinetic interactions between candesartan and amlodipine following multiple oral administrations in healthy subjects

Kim¹,

Kim²,

Huh³

et al. 2018

DDDT

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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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“…In the Caco-2 cell model, candesartan cilexetil not only is absorbed by passive diffusion across the membrane but also is a substrate of the energydependent intestinal efflux transporter P-glycoprotein (Pg-P) and a Pg-P inhibitor. [23][24][25] The absorption of candesartan cilexetil is enhanced by Pg-P inhibitors, such as cyclosporine A and verapamil. 23 We suggest that the main mechanism involved in the decrease in candesartan bioavailability with SR may be the modulation of Pg-P activity or expression by SR/SD state, as suggested for verapamil and quinidine, [5][6][7] which are both Pg-P and cytochrome P 3A4 (CYP3A4) substrates.…”

Section: Pharmacokinetic Consequences Of Differences In Dietary Sodiumentioning

confidence: 99%

“…[23][24][25] The absorption of candesartan cilexetil is enhanced by Pg-P inhibitors, such as cyclosporine A and verapamil. 23 We suggest that the main mechanism involved in the decrease in candesartan bioavailability with SR may be the modulation of Pg-P activity or expression by SR/SD state, as suggested for verapamil and quinidine, [5][6][7] which are both Pg-P and cytochrome P 3A4 (CYP3A4) substrates. A high-sodium diet decreases the plasma concentration of oral quinidine by ≈20% 5,7 and that of oral verapamil by ≈60%.…”

Section: Pharmacokinetic Consequences Of Differences In Dietary Sodiumentioning

confidence: 99%

Effect of Contrasted Sodium Diets on the Pharmacokinetics and Pharmacodynamic Effects of Renin–Angiotensin System Blockers

Azizi

Blanchard²,

Wuerzner³

et al. 2013

Hypertension

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There is considerable between-subject variability in the hemodynamic, cardiac, and renal responses to reninangiotensin system (RAS) blockers, and the contribution of the RAS to blood pressure (BP) control and other vascular, cardiac, and renal functions varies greatly between diseases and individuals.1 Age, genetic factors, ethnicity, and dietary sodium intake, in particular, are the principal factors influencing basal RAS status, which, in turn, is one of the major determinants of the pharmacodynamic effects of RAS blockers.1 Indeed, the hemodynamic, cardiac, and nephroprotective effects of RAS blockers are enhanced by the combination of these drugs with a low-sodium diet or diuretics because of RAS activation. [1][2][3][4] A pharmacokinetic interaction with the sodium content of the diet has been reported for drugs that do not interfere with the RAS. [5][6][7] We therefore compared the effect of contrasted sodium diets on the pharmacokinetics of single oral doses of various RAS blockers administered to normotensive healthy male subjects: an angiotensin-converting enzyme inhibitor (ramipril) and 2 different angiotensin II receptor blockers (candesartan cilexetil and valsartan). We selected 2 different angiotensin II receptor blockers to investigate whether in a same class, drugs with different physicochemical properties and pharmacokinetic profiles could be affected differently by the sodium content of the diet. To further understand the effects of sodium balance on the pharmacokinetics of these cardiovascular drugs, we also evaluated the effects of dietary sodium on atenolol, a selective β1-adrenergic blocker, that is absorbed passively through the intestinal wall 8 and is excreted unchanged by the kidney after glomerular filtration.9 Thus, any change in urinary excretion of atenolol with the sodium content of the diet should directly reflect a change in the net intestinal absorption of the drug in healthy subjects with Abstract-Dietary sodium, the main determinant of the pharmacodynamic response to renin-angiotensin system blockade, influences the pharmacokinetics of various cardiovascular drugs. We compared the effect of contrasted sodium diets on the pharmacokinetics of single oral doses of 8 mg candesartan cilexetil, 160 mg valsartan, 10 mg ramipril, and 50 mg atenolol administered to 64 (16 per group) normotensive male subjects randomly assigned to sodium depletion (SD) or sodium repletion (SR) in a crossover study. Pharmacodynamic response was assessed as the increase in plasma renin concentration for renin-angiotensin system blockers and electrocardiographic changes in PR interval duration for atenolol. The area under the curve (AUC) for plasma candesartan and atenolol concentrations was significantly lower for SR than for SD (respective ratios of AUC This trial is registered at ClinicalTrials.gov with trial identifier NCT00310778

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Transport characteristics of candesartan in human intestinal Caco‐2 cell line

Cited by 25 publications

References 16 publications

No pharmacokinetic interactions between candesartan and amlodipine following multiple oral administrations in healthy subjects

No pharmacokinetic interactions between candesartan and amlodipine following multiple oral administrations in healthy subjects

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

Effect of Contrasted Sodium Diets on the Pharmacokinetics and Pharmacodynamic Effects of Renin–Angiotensin System Blockers

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