Loss of orally administered drugs in GI tract

Gavhane, Yogeshkumar Nanasaheb; Yadav, Adhikrao Vyankatrao

doi:10.1016/j.jsps.2012.03.005

Cited by 129 publications

(81 citation statements)

References 94 publications

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“…Initial disintegration of LCP-Tacro tablets has been shown to occur in the stomach and/or proximal small bowel but complete disintegration (and presumably optimal absorption) [41] occurs in the distal small bowel or the colon (FIGURE 2) [34]. There appears to be less gut CYP3A4 activity in the distal portions of the gastrointestinal system [42] and thus less pre-systemic metabolism of tacrolimus, resulting in lower clearance and further increased bioavailability.…”

Section: Pks and Metabolismmentioning

confidence: 99%

Once-daily LCP-Tacro MeltDose tacrolimus for the prophylaxis of organ rejection in kidney and liver transplantations

Grinyó

Petruzzelli

2014

Expert Review of Clinical Immunology

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Tacrolimus is a cornerstone of the immunosuppression regimen for prevention of allograft rejection in kidney and liver transplantations, with efficacy proven in many clinical trials. The currently available and extensively used tacrolimus formulations are flawed by large inter-and intra-individual variability, low bioavailability, wide peak-to-trough fluctuations and a narrow therapeutic index. Drug delivery technology can significantly impact the pharmacologic action of a drug, influencing its pharmacokinetic and subsequent therapeutic profile. LCP-Tacro is a novel, prolonged-release, MeltDose Ò formulation of tacrolimus designed for once-daily administration. A hallmark differentiation between this formulation and other once-and twice-daily tacrolimus products is the proprietary MeltDose drug delivery technology which is designed to improve the bioavailability of drugs with low water solubility. Considering the studies conducted to date, once-daily LCP-Tacro has shown improved pharmacokinetic properties, rapid achievement of therapeutic trough levels, consistent exposure, non-inferior efficacy and similar safety, with lower tacrolimus dose than other tacrolimus formulations. World-wide there were an estimated 77,800 kidney transplants performed in 2012 (69% of all transplants) and 23,986 liver transplants (21% of all transplants) [1]. Data from the US show that, in 2013 more than half of the 28,953 transplants performed were kidney transplants (58.3%, n = 16,894) [2]; liver transplants were the next most frequent, comprising 22.2% (n = 6455) of all US transplants [2]. The number of individuals in need of organ transplantation outweighs the availability of organs -as of June 2014; data from the Organ Procurement and Transplantation Network showed that 100,967 individuals were on the waitlist for a kidney transplant and 15,758 individuals were on the waitlist for a liver transplant [3]. For individuals who receive a transplant, lifelong administration of immunosuppressive medications are required to prevent organ rejection. The arsenal of immunosuppressive drugs has evolved greatly since the beginnings of successful organ transplantation. A combination of azathioprine and corticosteroids was the original mainstay regimen in the early period of organ transplantation. A major advance in immunosuppression for prevention of allograft rejection came in the late 1970's with the advent of the calcineurin inhibitor (CNI) cyclosporine A [4][5][6]. The 'cyclosporine era' of the 1980's saw greatly improved short-and mid-term graft survival following transplantation. Immunosuppressive drugs have continued to evolve and the availability of improved drugs and regimens has contributed largely to the current high short-and long-term survival rates (survival following living donor transplant, 1-year kidney: 98%; 5-year kidney: 90%; 1-year liver: 90%; 5-year liver: 77%) [2]. In 1994, the EMA approved another CNI, tacrolimus, , Astellas Pharma US, Inc.), for the prophylaxis of organ rejection in kidney, liver and heart transplant ...

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Section: Pks and Metabolismmentioning

confidence: 99%

Once-daily LCP-Tacro MeltDose tacrolimus for the prophylaxis of organ rejection in kidney and liver transplantations

Grinyó

Petruzzelli

2014

Expert Review of Clinical Immunology

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“…The administration of drugs through the buccal route shows better patient acceptance when compared with vaginal, rectal and ocular routes, improving the patient compliance to treatment due to the ease and comfort of the administration [26,27]. The advantages of the buccal delivery include the direct absorption of drugs into the systemic circulation due to the good blood irrigation of the oral cavity, the avoidance of significant degradation of the drug as occurs by the high enzyme content and acid environment present in the gastrointestinal tract when drugs are absorbed in the intestine, and also the avoidance of the hepatic first-pass metabolism [28]. In addition, the rate of drug absorption when administered by the buccal route is not influenced by the gastric emptying rate as observed in the oral administration.…”

Section: Advantages Of Buccal Drug Deliverymentioning

confidence: 99%

“…As aforementioned, the buccal delivery may lead to drug degradation, decreasing its bioavailability. For instance, the buccal mucosa expresses less P-glycoprotein than the intestine, but the cytochrome P450 3A4 is similarly expressed in the oral mucosa and in the small intestine, so it is an additional barrier to overcome by the new drug delivery systems administered through the buccal route [28,33]. Another drawback is that the prolonged interaction of some drug delivery systems with the buccal mucosa may locally produce irritation and toxicity.…”

Section: Disadvantages Of Buccal Drug Deliverymentioning

confidence: 99%

Novel and revisited approaches in nanoparticle systems for buccal drug delivery

Macedo

Castro

Roque

et al. 2020

Journal of Controlled Release

106

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The buccal route is considered patient friendly due to its non-invasive nature and ease of administration. Such delivery route has been used as an alternative for the delivery of drugs that undergo first-pass metabolism or are susceptible to pH and enzymatic degradation, such as occurs in the gastrointestinal tract. However, the drug concentration absorbed in the buccal mucosa is often low to obtain an acceptable therapeutic effect, mainly due to the saliva turnover, tongue and masticatory movements, phonation, enzymatic degradation and lack of epithelium permeation.Therefore, the encapsulation of drugs into nanoparticles is an important strategy to avoid such problems and improve their buccal delivery. Different materials from lipids to natural or synthetic polymers and others have been used to protect and deliver drugs in a sustained, controlled or targeted manner, and enhance their uptake through the buccal mucosa improving their bioavailability and therapeutic outcome. Overall, the main aim of this review is to perform an overview about the nanotechnological approaches developed so far to improve the buccal delivery of drugs. Herein, several types of nanoparticles and delivery strategies are addressed, and a special focus on pipeline products is also given.

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“…Routinely classical in vitro studies consist of drug exposure of liver microsomes, hepatocytes cultivated in suspension and in a monolayer in Petri dishes [44,45]. Routinely classical in vitro studies consist of drug exposure of liver microsomes, hepatocytes cultivated in suspension and in a monolayer in Petri dishes [44,45].…”

Section: Drug Absorptions and Bioavailabilities Of Omeprazole And Phementioning

confidence: 99%

“…Intestinal first-pass metabolism may reduce extensively the bioavailability of drugs even if this role is often underestimated in comparison with the hepatic first-pass effect. Routinely classical in vitro studies consist of drug exposure of liver microsomes, hepatocytes cultivated in suspension and in a monolayer in Petri dishes [44,45]. Moreover, in vitro and in vivo oral bioavailability extrapolations are calculated using separate in vitro data obtained from cultures of Caco-2 (mainly permeability data) and of hepatocytes (metabolism data) [43,46].…”

Section: Drug Absorptions and Bioavailabilities Of Omeprazole And Phementioning

confidence: 99%

Investigation of omeprazole and phenacetin first‐pass metabolism in humans using a microscale bioreactor and pharmacokinetic models

Bricks

Hamon

Fleury

et al. 2015

Biopharm & Drug Disp

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A new in vitro microfluidic platform (integrated insert dynamic microfluidic platform, IIDMP) allowing the co-culture of intestinal Caco-2 TC7 cells and of human primary hepatocytes was used to test the absorption and first-pass metabolism of two drugs: phenacetin and omeprazole. The metabolism of these drugs by CYP1A2, CYP2C19 and CYP3A4 was evaluated by the calculation of bioavailabilities and of intrinsic clearances using a pharmacokinetic (PK) model. To demonstrate the usefulness of the device and of the PK model, predictions were compared with in vitro and in vivo results from the literature. Based on the IIDMP experiments, hepatic in vivo clearances of phenacetin and omeprazole in the IIDMP were predicted to be 3.10 ± 0.36 and 1.46 ± 0.25 ml/min/kg body weight, respectively. This appeared lower than the in vivo observed data with values ranging between 11.9-19.6 and 5.8-7.5 ml/min/kg body weight, respectively. Then the calculated hepatic and intestinal clearances led to predicting an oral bioavailability of 0.85 and 0.77 for phenacetin and omeprazole versus 0.92 and 0.78 using separate data from the simple monoculture of Caco-2 TC7 cells and hepatocytes in Petri dishes. When compared with the in vivo data, the results of oral bioavailability were overestimated (0.37 and 0.71, respectively). The feasibility of co-culture in a device allowing the integration of intestinal absorption, intestinal metabolism and hepatic metabolism in a single model was demonstrated. Nevertheless, further experiments with other drugs are needed to extend knowledge of the device to predict oral bioavailability and intestinal first-pass metabolism.

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Loss of orally administered drugs in GI tract

Cited by 129 publications

References 94 publications

Once-daily LCP-Tacro MeltDose tacrolimus for the prophylaxis of organ rejection in kidney and liver transplantations

Once-daily LCP-Tacro MeltDose tacrolimus for the prophylaxis of organ rejection in kidney and liver transplantations

Novel and revisited approaches in nanoparticle systems for buccal drug delivery

Investigation of omeprazole and phenacetin first‐pass metabolism in humans using a microscale bioreactor and pharmacokinetic models

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