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Novel In Vitro-In Vivo Extrapolation (IVIVE) Method to Predict Hepatic Organ Clearance in Rat

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ABSTRACT

Purpose

Drug elimination in the liver consists of uptake, metabolism, biliary excretion, and sinusoidal efflux from the hepatocytes to the blood. We aimed to establish an accurate prediction method for liver clearance in rats, considering these four elimination processes. In vitro assays were combined to achieve improved predictions.

Methods

In vitro clearances for uptake, metabolism, biliary excretion and sinusoidal efflux were determined for 13 selected compounds with various physicochemical and pharmacokinetic properties. Suspended hepatocytes, liver microsomes and sandwich-cultured hepatocytes were evaluated as in vitro models. Based on the individual processes, in vivo hepatic clearance was calculated. Subsequently, the predicted clearances were compared with the corresponding in vivo values from literature.

Results

Using this in vitro-in vivo extrapolation method good linear correlation was observed between predicted and reported clearances. Linear regression analysis revealed much improved prediction for the novel method (r2 = 0.928) as compared to parameter analysis using hepatocyte uptake only (r2 = 0.600), microsomal metabolism only (r2 = 0.687) or overall hepatobiliary excretion in sandwich-cultured hepatocytes (r2 = 0.321).

Conclusions

In this new attempt to predict hepatic elimination under consideration of multiple clearance processes, in vivo hepatic clearances of 13 compounds in rats were well predicted using an IVIVE analysis method based on in vitro assays.

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Fig. 1

Abbreviations

A:

total intracellular amount of radioactivity in sandwich-cultured hepatocytes

ABC:

ATP binding cassette

ATP:

adenosintriphosphate

BCRP:

breast cancer resistance protein

BDDCS:

biopharmaceutics drug disposition classification system

BSEP:

bile salt export pump

C:

total intracellular concentration of radioactivity in sandwich-cultured hepatocytes

CLapp,met:

apparent metabolic clearance

CLh:

hepatic plasma clearance

CLh,int,in vitro :

hepatic intrinsic clearance predicted from in vitro assays

CLh,org,in vitro :

hepatic organ clearance predicted from in vitro assays

CLh,org,in vivo :

hepatic organ clearance based on blood concentrations

CLmet:

metabolic clearance

CLren:

renal clearance

CLsandwich:

transcellular hepatobiliary clearance

CLtot:

total organ plasma clearance

DDI:

drug-drug interaction

Er:

urinary excretion ratio

fu(hep):

unbound fraction in hepatocytes

fu(mic):

unbound fraction in liver microsomes

fu,b:

unbound fraction in blood

fu,p:

unbound fraction in plasma

IVIVE:

in vitro-in vivo extrapolation

kgbw:

kilogram body weight

KHB:

Krebs-Henseleit buffer

Km,bile:

affinity constant for the biliary excretion

Km,efflux:

affinity constant for the active sinusoidal efflux

Km,met:

metabolic affinity constant

Km,uptake:

affinity constant for the active uptake

LC-MS:

liquid chromatography coupled with mass spectrometry

logD:

distribution coefficient

LOQ:

limit of quantification

LSC:

liquid scintillation counting

MDR/Mdr:

multi-drug resistance protein

mRNA:

messenger ribonucleic acid

MRP/Mrp:

multi-drug resistance associated protein

N.A.:

not applicable

N.D.:

not determined

OATP/Oatp:

organic anion transporting polypeptide

PBPK:

physiologically based pharmacokinetics

PSapp,bile:

apparent biliary clearance

PSbile:

biliary clearance

PSefflux,active:

apparent sinusoidal active efflux clearance

PSefflux,passive:

sinusoidal passive efflux clearance

PSefflux,total:

apparent sinusoidal total efflux clearance

PSuptake,active:

apparent active uptake clearance

PSuptake,passive:

non-specific passive diffusion

PSuptake,total:

total apparent uptake clearance

Qh:

rat hepatic blood flow rate

R:

compound amount in bile pocket

radio-HPLC:

high performance liquid chromatography coupled with on-line radio detection

Rb:

blood-to-plasma concentration ratio

S:

nominal incubation concentration in buffer system

t:

incubation time

Vapp,met:

apparent metabolic velocity

Vc:

rat hepatocyte volume

Vmax,bile:

maximum velocity for the biliary excretion

Vmax,efflux:

maximum velocity for the active sinusoidal efflux

Vmax,met:

maximum metabolic velocity

Vmax,uptake:

maximum velocity for the active sinusoidal uptake

Vuptake,total:

total apparent uptake velocity

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ACKNOWLEDGMENTS & DISCLOSURES

The authors wish to acknowledge the many Novartis Drug Metabolism and Pharmacokinetic Department Scientists of Basel Switzerland who have supported generation of data used in these analyses. Special thanks go to Drs. Heike Gutmann, Joel Krauser and Birk Poller for their critical evaluation of this work.

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Correspondence to Ken-ichi Umehara.

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Umehara, Ki., Camenisch, G. Novel In Vitro-In Vivo Extrapolation (IVIVE) Method to Predict Hepatic Organ Clearance in Rat. Pharm Res 29, 603–617 (2012). https://doi.org/10.1007/s11095-011-0607-2

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