In Vitro-In Vivo Correlations of Hepatic Drug Clearance

ABSTRACTThe aim of the study was to quantitatively predict the clearance of three antibiotics, amikacin, vancomycin, and teicoplanin, during continuous hemodiafiltration (CHDF) and to propose their optimal dosage in patients receiving CHDF. For this goal,in vitroCHDF experiments with a polyacrylonitrile (PAN) membrane were first performed using these antibiotics, and then the clearances were compared within vivoCHDF situations determined in 16 critically ill patients. Thein vitroCHDF clearances were described as the product of the outflow rate of a drain (Qoutflow) and the drug unbound fraction in artificial plasma, indicating that drug adsorption to the PAN membrane has minor effect on drug clearance in our settings. The observedin vivoclearances also agreed very well with the predicted values, with a product ofQoutflowand plasma unbound fraction, when residual creatinine clearance (CLCR) was taken into account (within a range of 0.67- to 1.5-fold for 15 of 16 patients). Based on these results, a nomogram of the optimized dosages of amikacin, vancomycin, and teicoplanin was proposed, and it was evident thatQoutflowand residual CLCRare major determinants of the dosage and dosing interval for these antibiotics. Although the applicability needs to be confirmed with another type of membrane or higherQoutflow, our nomogram can help determine the dosage setting in critically ill patients receiving CHDF.

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Effect of Albumin on Human Liver Microsomal and Recombinant CYP1A2 Activities: Impact on In Vitro-In Vivo Extrapolation of Drug Clearance

Drug Metabolism and Disposition ◽

10.1124/dmd.111.044057 ◽

2012 ◽

Vol 40 (5) ◽

pp. 982-989 ◽

Cited By ~ 29

Author(s):

Nitsupa Wattanachai ◽

Wichittra Tassaneeyakul ◽

Andrew Rowland ◽

David J. Elliot ◽

Kushari Bowalgaha ◽

...

Keyword(s):

Human Liver ◽

Drug Clearance ◽

In Vivo Extrapolation

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Prediction of cytochrome P450-mediated drug clearance in humans based on the measured activities of selected CYPs

Bioscience Reports ◽

10.1042/bsr20171161 ◽

2017 ◽

Vol 37 (6) ◽

Cited By ~ 7

Author(s):

Jie Gao ◽

Jie Wang ◽

Na Gao ◽

Xin Tian ◽

Jun Zhou ◽

...

Keyword(s):

Cytochrome P450 ◽

Liver Microsomes ◽

Normal Liver ◽

Drug Clearance ◽

Cytochrome P450 Enzymes ◽

Simple Method ◽

Drug Metabolizing Enzyme ◽

Descriptive Models

Determining drug-metabolizing enzyme activities on an individual basis is an important component of personalized medicine, and cytochrome P450 enzymes (CYPs) play a principal role in hepatic drug metabolism. Herein, a simple method for predicting the major CYP-mediated drug clearance in vitro and in vivo is presented. Ten CYP-mediated drug metabolic activities in human liver microsomes (HLMs) from 105 normal liver samples were determined. The descriptive models for predicting the activities of these CYPs in HLMs were developed solely on the basis of the measured activities of a smaller number of more readily assayed CYPs. The descriptive models then were combined with the Conventional Bias Corrected in vitro–in vivo extrapolation method to extrapolate drug clearance in vivo. The Vmax, Km, and CLint of six CYPs (CYP2A6, 2C8, 2D6, 2E1, and 3A4/5) could be predicted by measuring the activities of four CYPs (CYP1A2, 2B6, 2C9, and 2C19) in HLMs. Based on the predicted CLint, the values of CYP2A6-, 2C8-, 2D6-, 2E1-, and 3A4/5-mediated drug clearance in vivo were extrapolated and found that the values for all five drugs were close to the observed clearance in vivo. The percentage of extrapolated values of clearance in vivo which fell within 2-fold of the observed clearance ranged from 75.2% to 98.1%. These findings suggest that measuring the activity of CYP1A2, 2B6, 2C9, and 2C19 allowed us to accurately predict CYP2A6-, 2C8-, 2D6-, 2E1-, and 3A4/5-mediated activities in vitro and in vivo and may possibly be helpful for the assessment of an individual’s drug metabolic profile.

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967 OXYGEN-MEDIATED ENHANCEMENT OF PRIMARY HEPATOCYTE METABOLISM, FUNCTIONAL POLARIZATION, AND GENE EXPRESSION: ACHIEVING IN VIVO LEVELS OF DRUG CLEARANCE AND HCV INFECTION IN VITRO

Journal of Hepatology ◽

10.1016/s0168-8278(10)60968-3 ◽

2010 ◽

Vol 52 ◽

pp. S374 ◽

Cited By ~ 1

Author(s):

Y. Nahmias

Keyword(s):

Gene Expression ◽

Drug Clearance ◽

Hcv Infection ◽

Primary Hepatocyte ◽

Hepatocyte Metabolism ◽

Functional Polarization

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The relationship between in vivo nasal drug clearance and in vitro nasal mucociliary clearance: Application to the prediction of nasal drug absorption

European Journal of Pharmaceutical Sciences ◽

10.1016/j.ejps.2018.01.032 ◽

2018 ◽

Vol 117 ◽

pp. 21-26 ◽

Cited By ~ 5

Author(s):

Daisuke Inoue ◽

Akiko Tanaka ◽

Shunsuke Kimura ◽

Akiko Kiriyama ◽

Hidemasa Katsumi ◽

...

Keyword(s):

Drug Absorption ◽

Mucociliary Clearance ◽

Drug Clearance ◽

The Relationship ◽

Nasal Drug Absorption ◽

Nasal Mucociliary Clearance

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Evaluating Lean Liver Volume as a Potential Scaler for In Vitro-In Vivo Extrapolation of Drug Clearance in Obesity Using the Model Drug Antipyrine

Current Drug Metabolism ◽

10.2174/1389200221666200515105800 ◽

2020 ◽

Vol 21 (10) ◽

pp. 746-750

Author(s):

Jaydeep Sinha ◽

Stephen B. Duffull ◽

Bruce Green ◽

Hesham S. Al-Sallami

Keyword(s):

Liver Volume ◽

Drug Clearance ◽

Liver Fat ◽

Obese Patients ◽

Liver Size ◽

Total Liver Volume ◽

Model Drug ◽

In Vivo Extrapolation

Background : In vitro-in vivo extrapolation (IVIVE) of hepatic drug clearance (>CL) involves the scaling of hepatic intrinsic clearance (CLint,uH) by functional liver size, which is approximated by total liver volume (LV) as per the convention. However, in most overweight and obese patients, LV includes abnormal liver fat, which is not thought to contribute to drug elimination, thus overestimating drug CL. Therefore, lean liver volume (LLV) might be a more appropriate scaler of CLint,uH. Objective : The objective of this work was to assess the application of LLV in CL extrapolation in overweight and obese patients (BMI >25 kg/m2) using a model drug antipyrine. Methods: Recently, a model to predict LLV from patient sex, weight, and height was developed and evaluated. In order to assess the LLV model’s use in IVIVE, a correlation-based analysis was conducted using antipyrine as an example drug. Results : In the overweight group (BMI >25 kg/m2), LLV could describe 36% of the variation in antipyrine CL (R2 = 0.36), which was >2-fold higher than that was explained by LV (R2 = 0.17). In the normal-weight groupjats:(BMI ≤25 kg/m2), the coefficients of determination were 58% (R2 = 0.58) and 43% (R2= 0.43) for LLV and LV, respectively. Conclusion : The analysis indicates that LLV is potentially a more appropriate descriptor of functional liver size than LV, particularly in overweight individuals. Therefore, LLV has a potential application in IVIVE of CL in obesity.

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