Mucosal permeability of water‐soluble drugs in the equine jejunum: a preliminary investigation

Davis, Jennifer L.; Little, Dianne; Blikslager, Anthony T.; Papich, Mark G.

doi:10.1111/j.1365-2885.2006.00757.x

Cited by 32 publications

(29 citation statements)

References 30 publications

(51 reference statements)

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“…Due to the high lipophilicity of DIM-P and likely passive transcellular mechanism of absorption, we attempted to derive a potential In Vitro–In Vivo Correlation (IVIVC) between the in vitro permeability, and the oral absorption pharmacokinetics (Davis et al, 2006). We employed deconvolution of i.v.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic evaluation and In Vitro–In Vivo Correlation (IVIVC) of novel methylene-substituted 3,3′ diindolylmethane (DIM)

Patel

Spencer

Chougule

et al. 2012

European Journal of Pharmaceutical Sciences

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Purpose 3,3′-Diindolylmethane (DIM) is the major in vivo product of the acid-catalyzed oligomerization of indole-3-carbinol present in cruciferous vegetables. 1, 1-bis (3′-indolyl)-1-(p-substituted phenyl) methanes [C-substituted diindolylmethanes (C-DIMs)] are a new class of anticancer compounds derived from indole 3-carbinol. Despite rapidly increasing knowledge regarding mechanisms responsible for the chemopreventive properties of DIM-C-pPhC6H5, there have been relatively few studies determining the absorption and pharmacokinetic properties of DIM-C-pPhC6H5 to explore its clinical utility. Methods In this study, we assessed the solubility, lipophilicity and Caco-2 cell permeability of methylene-substituted DIM. Pharmacokinetic properties in rats were determined following i.v. and oral administration of a novel analog of DIM. Pharmacokinetic parameters were determined using noncompartmental and compartmental techniques with WinNonlin® 5.0 software. To explore potential In Vitro–In Vivo Correlation (IVIVC) between the in vitro permeability values, and the oral absorption pharmacokinetics, we employed deconvolution of i.v. and oral data using a three compartment Exact Loo–Riegelman method. Results The oral absorption and disposition were described by a three compartment model with combined zero-order/Michaelis–Menten limited systemic uptake using differential equations, at physiologically relevant doses. The saturation model obtained accounts for a nonlinear change in Cmax/Dose, and the absolute bioavailability (0.13 ± 0.06) was also dose dependent. The absorption rate profile of DIMC-pPhC6H5 across Caco-2 cells was significantly different than in vivo. Conclusions: The pharmacokinetic absorption model presented represents a useful basis for obtaining plasma level predictability for poorly bioavailable, highly lipophilic drugs, such as the DIM analog DIM-C-pPhC6H5.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic evaluation and In Vitro–In Vivo Correlation (IVIVC) of novel methylene-substituted 3,3′ diindolylmethane (DIM)

Patel

Spencer

Chougule

et al. 2012

European Journal of Pharmaceutical Sciences

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“…No studies about metronidazole permeability in Caco-2 cells were identified. A mucosal permeability study of several drugs, including metronidazole, was performed in the equine jejunum 32 and metronidazole exhibited unusual high permeability when compared with the other drugs (cephalexin, marbofloxacin, and fluconazole), with effective permeability (P eff ) around 9 × 10 −5 cm/s. According to the authors, the high permeability of metronidazole may be due to a direct cytotoxic effect on the mucosal epithelial cells, and also to absorption by paracellular transport, in addition to transcellular transport.…”

Section: Permeabilitymentioning

confidence: 99%

“…The only metronidazole intestinal permeability study found, performed in equine jejunum, showed the drug to be highly permeable. 32 No permeability studies of metronidazole in Caco-2 cells were identified, but the demonstration of complete absorption in humans is preferred for BCSbased biowaiver applications. 4 In addition, metronidazole undergoes extensive hepatic metabolism, [68][69][70] indicating also high GI permeability.…”

Section: Permeabilitymentioning

confidence: 99%

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Metronidazole

Rediguieri¹,

Porta

Nunes³

et al. 2011

Journal of Pharmaceutical Sciences

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“…We have justified this approach because a comparison of drug absorption across human colonic epithelium cell layers (Caco-2 cell line) to absorption across canine colon tissue did not show a relationship (19). The Ussing chamber technique, which has been evaluated for other veterinary species (20), has not been applicable for canine studies (21) because of the fragility of the tissue. Membrane damage that occurs prevents permeability measurements using this technique in dogs (21).…”

Section: Introductionmentioning

confidence: 99%

Applying Biopharmaceutical Classification System (BCS) Criteria to Predict Oral Absorption of Drugs in Dogs: Challenges and Pitfalls

Papich

Martinez

2015

AAPS J

112

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Abstract. The Biopharmaceutical Classification System (BCS) has been a prognostic tool for assessing the potential effects of formulation on the human drug oral bioavailability. When used in conjunction with in vitro dissolution tests, the BCS can support the prediction of in vivo product performance and the development of mechanistic models that support formulation assessments through the generation of Bwhat if^scenarios. To date, the applicability of existing human BCS criteria has not been evaluated in dogs, thereby limiting its use in canine drug development. Therefore, we examined 50 drugs for which absolute bioavailability (F) was available both in dogs and humans. The drugs were also evaluated for any potential association between solubility (calculated from the dose number, Do) or lipophilicity (LogP) and F in dogs. In humans, solubility is determined in 250 mL of fluid. However, the appropriate volume for classifying drug solubility in dogs has not been established. In this analysis, the estimated volume of a water flush administered to fasted dogs (6 mL) and a volume of 250 mL scaled to a Beagle dog (35 mL) were examined. In addition, in humans, a Do value greater than 1.0 is used to define a compound as highly soluble and a LogP value greater than 1.72 as high permeability. These same criteria were applied for defining highly soluble and highly permeable in dogs. Whether using 35 or 6 mL to determine Do, the canine solubility classification remained unchanged for all but seven compounds. There were no clear associations between a drug's F in dogs and humans or between the canine value of F and either its human BCS classification, its LogP value, or the canine Do estimate. There was a tendency for those drugs with canine values of F equal to or greater than 80% to have LogP values equal to or greater than 1.0. Exceptions to this observation tended to be those compounds known to be absorbed via mechanisms other than passive diffusion (e.g., via transporters or paracellular transporters). Although there are limitations to the approach used in this study, the results of our assessment strongly suggest that the human BCS classification system requires substantial modification before it can be reliably applied to dogs.

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Mucosal permeability of water‐soluble drugs in the equine jejunum: a preliminary investigation

Cited by 32 publications

References 30 publications

Pharmacokinetic evaluation and In Vitro–In Vivo Correlation (IVIVC) of novel methylene-substituted 3,3′ diindolylmethane (DIM)

Pharmacokinetic evaluation and In Vitro–In Vivo Correlation (IVIVC) of novel methylene-substituted 3,3′ diindolylmethane (DIM)

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Metronidazole

Applying Biopharmaceutical Classification System (BCS) Criteria to Predict Oral Absorption of Drugs in Dogs: Challenges and Pitfalls

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