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The Role of Permeability in Drug ADME/PK, Interactions and Toxicity—Presentation of a Permeability-Based Classification System (PCS) for Prediction of ADME/PK in Humans

Pharmaceutical Research volume 25, pages 625–638 (2008)Cite this article

Abstract

Purpose

The objective was to establish in vitro passive permeability (P e) vs in vivo fraction absorbed (f a)-relationships for each passage through the human intestine, liver, renal tubuli and brain, and develop a P e-based ADME/PK classification system (PCS).

Materials and Methods

P e- and intestinal f a-data were taken from an available data set. Hepatic f a was calculated based on extraction ratios of the unbound fraction of drugs (with support from animal in vivo uptake data). Renal f a (reabsorption) was estimated using renal pharmacokinetic data, and brain f a was predicted using animal in vitro and in vivo brain P e-data. Hepatic and intestinal f a-data were used to predict bile excretion potential.

Results

Relationships were established, including predicted curves for bile excretion potential and minimum oral bioavailability, and a 4-Class PCS was developed: I (very high P e; elimination mainly by metabolism); II (high P e) and III (intermediate P e and incomplete f a); IV (low P e and f a). The system enables assessment of potential drug–drug transport interactions, and drug and metabolite organ trapping.

Conclusions

The PCS and high quality P e-data (with and without active transport) are believed to be useful for predictions and understanding of ADME/PK, elimination routes, and potential interactions and organ trapping/toxicity in humans.

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Abbreviations

ADME/PK:

AbsorptionDistributionMetabolismExcretion/Pharmacokinetics

a.s.:

active secretion

BBB:

blood–brain barrier

BCS:

Biopharmaceutics Classification System

BDDCS:

Biopharmaceutics Drug Disposition Classification System

BUI:

brain uptake index

Cbl/Cpl :

blood-to-plasma concentration ratio

CL:

clearance

CLH :

hepatic CL

CLint :

intrinsic CL

CLint,secr :

renal tubular secretion CLint

CLR :

renal CL

E H :

hepatic extraction ratio

EHC:

enterohepatic circulation

E u,H :

E H for unbound drug

E max,bile :

maximum bile excretion potential

E u,R :

renal extraction ratio for unbound drug

E 1st-pass :

first-pass extraction ratio

F :

oral bioavailability

f a :

fraction absorbed

f a,B :

brain f a

f a,H :

hepatic f a

f a,I :

intestinal f a

f e :

fraction of intravenous dose excreted unchanged in urine

F min :

minimum F

fra :

fraction reabsorbed

f ra,bile :

fraction reabsorbed from the intestines following bile excretion

f ra,R :

fraction reabsorbed in the renal tubuli

f u :

unbound fraction

f u,bl :

f u in blood

f u,pl :

f u in plasma

GFR:

glomerular filtration rate

GI:

gastrointestinal

MDCK:

Madin–Darby canine kidney cells

MW:

molecular weight

P e :

permeability

PCS:

P e-based Classification System

P e S :

uptake CL (permeability–surface area product)

P e50 :

P e corresponding to a f a (or f ra) of 0.50

PSA:

polar surface area

Q :

blood flow rate

Q B :

brain Q

Q H :

hepatic Q

Q R :

renal Q

S :

surface area

S B :

brain S

TT:

transit time

\(t_{{1 \mathord{\left/ {\vphantom {1 2}} \right. \kern-\nulldelimiterspace} 2}} ,\) :

half-life

λ :

slope factor

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Acknowledgments

The author greatly acknowledges Professor Per Artursson at Uppsala University, Sweden, Associate Professor Anna-Lena Ungell at AstraZeneca R&D Mölndal, Sweden, and Doctors Lovisa Afzelius and Janet Hoogstraate at AstraZeneca R&D Södertälje, Sweden, for reviewing the manuscript, for valuable comments and advise, and for support.

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    Urban Fagerholm

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Fagerholm, U. The Role of Permeability in Drug ADME/PK, Interactions and Toxicity—Presentation of a Permeability-Based Classification System (PCS) for Prediction of ADME/PK in Humans. Pharm Res 25, 625–638 (2008). https://doi.org/10.1007/s11095-007-9397-y

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Key words

  • absorption
  • classification system
  • drug–drug transport interactions
  • permeability
  • prediction