Pharmacokinetic Analysis of Concentration Data of Drugs with Irregular Absorption Profiles Using Multi-Fraction Absorption Models

Murata, Katsuyuki; Noda, Kohei; Kohno, Keiichi; Samejima, Masayoshi

doi:10.1002/jps.2600760205

Cited by 44 publications

(23 citation statements)

References 7 publications

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“…Recently, the use of simulated intestinal fluid under fasting or fed conditions has enabled the estimation of drug dissolution in the gastrointestinal tract in vivo (5,6). The gastrointestinal transit of drugs also concerns time profiles of drug concentration in the gastrointestinal tract and has been investigated extensively, usually from time profiles of the blood concentration of orally administered marker drugs such as acetaminophen, sulfasalazine, or polyethylene glycol 4000 (7)(8)(9).…”

mentioning

confidence: 99%

PET Imaging of the Gastrointestinal Absorption of Orally Administered Drugs in Conscious and Anesthetized Rats

Yamashita¹,

Takashima²,

Kataoka³

et al. 2011

J Nucl Med

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This study assessed the process of gastrointestinal drug absorption in vivo using PET. Methods: 18 F-FDG was used as a model probe and was orally administered to rats as a solution. PET scans were obtained of the whole body and abdominal region under conscious and anesthetized conditions. Blood samples were routinely taken from the femoral vein during scanning. The rate of gastric emptying and intestinal absorption of 18 F-FDG was estimated from the time profiles of radioactivity in the stomach and small intestine. In addition, nonradiolabeled 2-fluoro-2-deoxy-D-glucose (2-FDG) was used in an intestinal closed-loop experiment to compare the intestinal permeability of 2-FDG with that of D-glucose. Results: In conscious rats, gastrointestinal absorption of 18 F-FDG was rate-limited by the process of intestinal membrane permeation, because the permeability of 2-FDG through the intestinal membrane was low compared with that of D-glucose. In anesthetized rats, the gastric emptying rate of 18 F-FDG decreased dramatically whereas the intestinal absorption rate constant was not significantly different from that in conscious rats. As a result, the rate-limiting step of gastrointestinal absorption of 18 F-FDG was shifted to the gastric emptying process by anesthesia. Conclusion: PET technology is a powerful tool for in vivo analysis of the gastrointestinal absorption of orally administered drugs. Gast rointestinal absorption of orally administered drugs involves many processes that occur in parallel or sequentially, starting with the disintegration and dissolution of drugs in the gastrointestinal fluid and continuing to the transit of drugs in the gastrointestinal tract, permeation of drug molecules through the intestinal membrane, and metabolism in the intestine or liver. The rate and amount of drug absorption into systemic circulation are defined as total outputs of these processes. Except for first-pass metabolism, the rate and amount of drug absorption are expressed by the following equations, Absorption rate 5 P eff · S · C E q : 1where P eff is an effective permeability of drugs, S is a surface area of the intestinal membrane, and C is the luminal concentration of drugs. AUC expresses the area under the drug concentration-time curve in the gastrointestinal tract during the intestinal transit time, t. To calculate the fraction of drugs absorbed in each segment of the gastrointestinal tract, these parameters in equations should be assessed. The P eff of drugs can be estimated by in vitro or in situ experiments (1,2). At pharmaceutical companies, in vitro permeation assays with cultured cell systems such as Caco2 or Madin-Darby canine kidney cell monolayers are widely used to determine drug permeability (3,4). Luminal concentration is affected by various factors, including drug solubility, dissolution rate, and the volume of gastrointestinal fluid. Among these factors, drug solubility and dissolution profiles can be evaluated by in vitro experiments. Recently, the use of simulated intestinal fluid under fasting or fed ...

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mentioning

confidence: 99%

PET Imaging of the Gastrointestinal Absorption of Orally Administered Drugs in Conscious and Anesthetized Rats

Yamashita¹,

Takashima²,

Kataoka³

et al. 2011

J Nucl Med

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“…This kind of simple model cannot describe the irregular shape in the plasma concentration, which is often observed. Therefore, several models were proposed to analyze the plasma profile, [8][9][10][11] but they are not necessarily based on the practical phenomena, i.e. GI transit and site-different drug absorbability.…”

mentioning

confidence: 99%

“…12) Although several efficient methods to estimate the absorption of orally administered drug by analyzing the GI disposition following oral administration (GI disposition analysis) have been reported, some are only focused on the gastric emptying based on a model having a stomach and an intestine compartment. 13,14) The other one estimated the intestinal transit of a drug using polyethylene glycol 4000 as a nonabsorbable marker, 10) but the actual data of intestinal transit were not utilized enough to analyze and predict the drug absorption kinetics. Although the analytical procedures for plasma profile of a drug absorbed from successive absorption sites along the GI tract have been also reported, [16][17][18] they just showed the concept and/or simulation study based on the model.…”

mentioning

confidence: 99%

Gastrointestinal Transit and Drug Absorption

Kimura

Higaki

2002

Biological & Pharmaceutical Bulletin

173

114

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Oral drug administration is the most convenient and common for drug therapy and it is, therefore, very important and useful to estimate the absorbability of drugs and to predict the plasma concentration profile of drugs after oral administration for the development of novel drugs and/or novel dosage form and the designation of the dosage regimen. Generally, the absorbability of drugs has been estimated by in-situ recirculation studies, in-situ closed loop studies or the analysis by the simple compartment model. The information which can be obtained from these approaches is usually an absorption rate constant, ka. The ka value is generally the averaged one throughout the intestinal tract. However, there is the site-difference in drug absorbability [1][2][3][4] and variable residence time of drugs in each segment must make the contribution of each segment to drug absorption changed, resulting in the different absorbability as a whole. As for the drug absorption after oral administration, the gastrointestinal (GI) transit of a drug is also an important factor to determine the drug absorption and is so variable, as was influenced by not only individual differences, 5) but also the dosage conditions like meals, 6) disease states 7) and so on. Therefore, the absorbability and the residence time in each segment are the major determining factors for drug absorption after oral administration and very important for the analysis of drug absorption kinetics and the estimation of, and the prediction of plasma concentration profiles of drugs. However, the analysis and the estimation of drug absorption after oral administration have been usually performed by a simple compartment model, where even a process of gastric emptying is not included often. This kind of simple model cannot describe the irregular shape in the plasma concentration, which is often observed. Therefore, several models were proposed to analyze the plasma profile, [8][9][10][11] but they are not necessarily based on the practical phenomena, i.e. GI transit and site-different drug absorbability.We have developed a GI-Transit-Absorption (GITA) Model containing the GI transit and absorption processes to analyze and predict the plasma concentration profile after oral administration of aqueous drug solution.12) Although several efficient methods to estimate the absorption of orally administered drug by analyzing the GI disposition following oral administration (GI disposition analysis) have been reported, some are only focused on the gastric emptying based on a model having a stomach and an intestine compartment. 13,14) The other one estimated the intestinal transit of a drug using polyethylene glycol 4000 as a nonabsorbable marker, 10) but the actual data of intestinal transit were not utilized enough to analyze and predict the drug absorption kinetics. Although the analytical procedures for plasma profile of a drug absorbed from successive absorption sites along the GI tract have been also reported, [16][17][18] they just showed the concept and/or simulation stu...

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“…For this particular scenario, the time point, Tau, represents a change-point in the model, where the drug-release mechanism changes from phase-1 control (eg, diffusional burst) to phase-2 control (eg, matrix erosion). Murata et al 11 further described this scenario as shown in Figure 3.…”

Section: Model-dependent Analysis Of In Vivo Release Kineticsmentioning

confidence: 93%

“…[10][11][12] For PLA 100, PLGA 85:15, and Sandostatin LAR microspheres, a proposed model was developed as an adaptation of the pharmacokinetic analysis described by Murata et al 11 for the characterization of irregular absorption profiles. The model centers on a successive fractional release method to convey the phases of drug release from a dosage form (ie, burst release, diffusion-controlled release, and erosion-controlled release for microspheres).…”

Section: Model-dependent Analysis Of In Vivo Release Kineticsmentioning

confidence: 99%

In vivo release kinetics of octreotide acetate from experimental polymeric microsphere formulations using oil/water and oil/oil processes

et al. 2004

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The purpose of the present study was to characterize the in vivo release kinetics of octreotide acetate from microsphere formulations designed to minimize peptide acylation and improve drug stability. Microspheres were prepared by a conventional oil/water (o/w) method or an experimental oil/oil (o/o) dispersion technique. The dosage forms were administered subcutaneously to a rat animal model, and serum samples were analyzed by radioimmunoassay over a 2-month period. An averaged kinetic profile from each treatment group, as a result, was treated with fractional differential equations. The results indicated that poly(l-lactide) microspheres prepared by the o/o dispersion technique provided lower area under the curve (AUC) values during the initial diffusion-controlled release phase, 7.79 ng×d/mL, versus 75.8 ng×d/mL for the o/w batch. During the subsequent erosion-controlled release phase, on the other hand, the o/o technique yielded higher AUC values, 123 ng×d/mL, versus 42.2 ng×d/mL for the o/w batch. The differences observed between the 2 techniques were attributed to the site of drug incorporation during the manufacturing process, given that microspheres contain both porous hydrophilic channels and dense hydrophobic matrix regions. An o/o dispersion technique was therefore expected to produce microspheres with lower incorporation in the aqueous channels, which are responsible for diffusion-mediated drug release.

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Pharmacokinetic Analysis of Concentration Data of Drugs with Irregular Absorption Profiles Using Multi-Fraction Absorption Models

Cited by 44 publications

References 7 publications

PET Imaging of the Gastrointestinal Absorption of Orally Administered Drugs in Conscious and Anesthetized Rats

PET Imaging of the Gastrointestinal Absorption of Orally Administered Drugs in Conscious and Anesthetized Rats

Gastrointestinal Transit and Drug Absorption

In vivo release kinetics of octreotide acetate from experimental polymeric microsphere formulations using oil/water and oil/oil processes

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