Clearance and bioavailability study through arterio-venous drug concentrations relationship

Fagiolino, Pietro; Vázquez, Marta; Eiraldi, Rosa

doi:10.1016/j.ejps.2013.01.016

Cited by 7 publications

(7 citation statements)

References 7 publications

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“…For this reason, it is not surprising to observe a clockwise hysteresis loop for the relationships between chloride and furosemide ERs (see Figure 3). This resembles what was observed when drug effect, or arterial drug concentration, versus venous drug concentration was graphed for nicotine [19]. Accordingly, furosemide ERs would surrogate their venous plasma concentrations.…”

Section: Sex-related Differences In Drug Absorption and Kidney Blood supporting

confidence: 63%

Section: Sex-related Differences In Drug Absorption and Kidney Blood mentioning

confidence: 99%

“…Each time the absorption resumes, a new increase in the arterial-venous difference occurs. Theoretical and experimental research dealt with this physiological phenomenon and with its consequence on drug action [18,19].According to this, furosemide would act before it could be excreted, since its arrival at the action sites from the capillaries took lesser time than its arrival at the end of the luminal space of renal tubules from the glomerulus. For this reason, it is not surprising to observe a clockwise hysteresis loop for the relationships between chloride and furosemide ERs (see Figure 3).…”

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confidence: 99%

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Sex-related in vitro/in vivo and PK/PD correlations after oral single dose furosemide administration

Magallanes¹,

Fagiolino²,

Vázquez³

et al. 2016

J Pharm Technol Drug Res

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Background: The goal of this study was to develop an in vivo-in vitro (IVIV) correlation, both in men and women, which allows constructing a model to predict bioequivalence assessments for drugs with narrow absorption windows. Besides, pharmacokinetic and pharmacodynamic equivalences were also investigated. Furosemide was chosen as a prototype. Methods: Twelve healthy Caucasian volunteers (8 women and 4 men) participated in a relative bioavailability study. Two oral formulations [Lasix ® (Reference, R) and Furosemide EFA ® (Test, T)] were administered under fasting conditions. Urinary excretion of unchanged drug (PK), and of chloride, sodium and potassium (PD) wasmonitored throughout time. PK and PD parameters were calculated from each respective excretion rate versus time curve. In vitro dissolution testing of both formulations was carried out using the USP apparatus 2 and 4 with fixed and variable dissolution media. Results: T and R could be considered bioequivalent since the 90% confidence intervals for the T/R ratio of geometric means for the area under the urinary drug excretion rate versus time curve and for the maximum excretion rate were within the 0.80-1.25 bioequivalence interval. However, T had faster initial absorption and higher levels in women, while R displayed such characteristics in men. Closer IVIV correlations in women were obtained when apparatus 4 with variable biorelevant dissolution media were used [going from fasting state simulated gastric fluid to fasting state simulated intestinal fluid]. Since R had faster disintegration time than T, a shorter stay of R under gastric conditions was required in order to obtain a good IVIV correlation in men. Saluretic effect displayed a typical clockwise hysteresis loop for the PKPD correlation assessed through chloride-versus-furosemide urinary excretion rates. Even though a higher amount of furosemide was excreted with the urine in men, differences in the excretion of electrolytes between sexes were almost negligible. Conclusions: Sex-differences in the gastrointestinal transit of formulations, under fasting conditions, determined the extent and the rate of furosemide absorption. The prolongation of the absorption process by mean of slowing the gastric emptying would make the formulation more effective. The USP-4 apparatus with variable dissolution media was able to discriminate the formulations even between sexes, becoming a promissory in vitro dissolution testing to predict bioequivalence. Keywords: Furosemide, oral absorption, IVIV and PKPD correlations, sex-by-formulation interaction, bioequivalence © 2016 Fagiolino et al; licensee Herbert Publications Ltd. This is an Open Access article distributed under the terms of Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). This permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. IntroductionFurosemide is a loop diuretic that is commonly used in the treatment of edematous states associated with car...

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Section: Sex-related Differences In Drug Absorption and Kidney Blood supporting

confidence: 63%

Section: Sex-related Differences In Drug Absorption and Kidney Blood mentioning

confidence: 99%

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confidence: 99%

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Sex-related in vitro/in vivo and PK/PD correlations after oral single dose furosemide administration

Magallanes¹,

Fagiolino²,

Vázquez³

et al. 2016

J Pharm Technol Drug Res

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“…Differences between the arterial and venous concentrations and potential models for inter-conversion of reported data have been described by a number of investigators ( 9 – 14 ). Many of these publications focus on the implications of these concentration differences for modelling of pharmacodynamics, and these models are generally empirical or compartmental in structure and are not easily applied to PBPK models.…”

Section: Introductionmentioning

confidence: 99%

Are Physiologically Based Pharmacokinetic Models Reporting the Right Cmax? Central Venous Versus Peripheral Sampling Site

Musther

Gill

Chetty

et al. 2015

AAPS J

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Physiologically based pharmacokinetic (PBPK) models can over-predict maximum plasma concentrations (Cmax) following intravenous administration. A proposed explanation is that invariably PBPK models report the concentration in the central venous compartment, rather than the site where the samples are drawn. The purpose of this study was to identify and validate potential corrective models based on anatomy and physiology governing the blood supply at the site of sampling and incorporate them into a PBPK platform. Four models were developed and scrutinised for their corrective potential. All assumed the peripheral sampling site concentration could be described by contributions from surrounding tissues and utilised tissue-specific concentration-time profiles reported from the full-PBPK model within the Simcyp Simulator. Predicted concentrations for the peripheral site were compared to the observed Cmax. The models results were compared to clinical data for 15 studies over seven compounds (alprazolam, imipramine, metoprolol, midazolam, omeprazole, rosiglitazone and theophylline). The final model utilised tissue concentrations from adipose, skin, muscle and a contribution from artery. Predicted Cmax values considering the central venous compartment can over-predict the observed values up to 10-fold whereas the new sampling site predictions were within 2-fold of observed values. The model was particularly relevant for studies where traditional PBPK models over-predict early time point concentrations. A successful corrective model for Cmax prediction has been developed, subject to further validation. These models can be enrolled as built-up modules into PBPK platforms and potentially account for factors that may affect the initial mixing of the blood at the site of sampling.Electronic supplementary materialThe online version of this article (doi:10.1208/s12248-015-9796-7) contains supplementary material, which is available to authorized users.

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“…This ratio should be approximately 1 or below 1 if there is no drug entrance. Due to the higher clearance that CBZ has after chronic administration, pre-dose S S /P fV should be theoretically much lower than 1 [19], but because of its inductive effect [14] the obtained value resulted practically 1 [18]. It is important to remark that to reach a reliable conclusion about overexpression of efflux carriers, S S /P fV must be determined when drug absorption is not operating.…”

Section: Saliva Drug Concentration and Saliva-to-plasma Level Ratiomentioning

confidence: 99%

Therapeutic Monitoring of Anticonvulsants: Use of Saliva as Biological Fluid

Vázquez¹,

Fagiolino²

2016

Epileptology - The Modern State of Science

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Plasma drug concentration is not homogeneous within the intravascular space, being the arterial P A ) concentrations higher or lower than that in veins P V ) depending on whether the samples are taken during the drug absorption or the elimination phases, respectively. However, blood samples are currently withdrawn from peripheral veins and total bound plus unbound) plasma drug concentration is assayed. Despite the fact that free plasma drug levels P fV ) are not determined in routine therapeutic drug monitoring TDM), they could be assayed for research purposes. Salivary drug concentrations S) approximate to their free plasma levels in the arteries of the great circulation. Saliva is recommended to be collected with stimulation to minimize the diference between the pHs of both luids saliva and blood), and thus, artery/vein-free drug concentration ratios P fA /P fV ) could be surrogated by the stimulated saliva/freeplasma in vein drug concentration ratios S S /P fV ). It is possible in this way not only to assess this S/P ratio but also to infer the brain B)/P fV ratio, which is actually the most relevant for antiepileptic drugs AEDs). Diferent cases of AEDs are considered in this review, taking into account their physiochemical properties and their ability to be transported by membrane carriers.

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Clearance and bioavailability study through arterio-venous drug concentrations relationship

Cited by 7 publications

References 7 publications

Sex-related in vitro/in vivo and PK/PD correlations after oral single dose furosemide administration

Sex-related in vitro/in vivo and PK/PD correlations after oral single dose furosemide administration

Are Physiologically Based Pharmacokinetic Models Reporting the Right Cmax? Central Venous Versus Peripheral Sampling Site

Therapeutic Monitoring of Anticonvulsants: Use of Saliva as Biological Fluid

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