Chemistry for Medicine 1
医用化学１(1st period, Friday)
November 16th, 2018
(Next time: Nov. 22nd)Interaction of particles and biointerface~For control of cellular uptake~ (continued)- Introduction to pharmacokinetics and pharmacodynamics-

Akihiro Kishimura(Associate Professor,
Katayama Laboratory)
kishimura.akihiro.776@m.kyushu-u.ac.jp

Introduction to Drug Delivery System(from the engineering viewpoint)5

Nov 2ndWhy size matters? ~ From the anatomic viewpoint(人体の構造とサイズ感)6

Nov 9thInteraction of particles and biointerface ~ For control
of cellular uptake (微粒子のバイオ界面との相互作用)7

Nov 16th

Introduction to pharmacokinetics andpharmacodynamics (PK/PD入門)

8

Nov 22th

Formulation design based on nanotechnology (ナノ剤形の設計と疾患治療)

Teaching material：Open access on BookRoll（e-learning system）
教材 - 教材一覧 - Others - 公開資料（岸村顕広）(Contents - List Contents - Others - 公開資料（岸村顕広）)Pattern recognition by macrophage
Macrophages or dendritic cells often recognize pathogens or foreign materials by“pattern recognition receptors (PRRs)”. This is a primitive part of the immune system
to know “nonself”.

Pathogen-associated molecular patterns (PAMPs)“Common sign” of bacteria (microbe-specific molecules) can be recognized by PAMPs.
1) Toll-like receptor (TLR)(membrane-bound)ex.) TLR2 : bacterial lipopeptides etc.
TLR4 : lipopolysaccharide of gram-negative bacteria etc.

2) C-type lectin receptors(CLR) (membrane-bound)ex.) Mannose receptor : the recognition motif for many viruses,
fungi and mycobacteria
DC-SIGN : Binding to HIV and hepatitis C (to promote to infect Tcell).
Dectin-1 : β-glucans of fungi and bacteria3) RIG-I-like receptors(Intracellular)

Recognition of viral double-stranded (ds) and single stranded RNA

4) NOD-like receptorsex.) NOD1, NOD2 : peptidoglycan motifs from bacterial cell

Scavenger receptors
A group of receptors that recognize modiﬁed (or oxidized) low-density lipoprotein,
apoptoXc cells, and pathogens.
- Many kinds. Mainly, they recognize negaXvely charged materials.
-

4

Type

Carrier

Energya. Passive transport
1) Simple diffusion

Transport across the membrane
Hydrophobic
compoundi) DissolutionNoNo
diffusionii) RestrictedNoNo
diffusion
By pore or(filtration)intercellular gapiii) Solvent
drag

No

No

Need

No

Active transportb. Active transport
1) Primary active
transport

Need

Need
Na+, K+, H+

Pump, ATPase2) Secondary active transporti) Symport

Need

Need

ii) Antiport

Need

Need

iii) Uniiport

Need

Need

Chargedcompound

The thermodynamic process driven byconcentraXon gradient, and/or electrochemical
gradient (down-hill transport). It involves noenergy consumpXon; but it is dependent on thepotenXal.
1-i): Only for hydrophobic small compounds, andgasses.
Facillitated transport: Protein channels or carriers
are required.

By pore orintercellular gap

2) Facilitateddiffusion

Passive transport

etc…

Energy-dependent process. Up-hill transport.
Speciﬁc protein carries/transporters are
required.
Primary: Directly utilizes ATP, GTP.
Secondary: The up-hill transport coupledwith the down-hill transport using
concentration gradient produced byprimary active transports (Na+, H+ gradient,etc..) (Symport, antiport). Uniport: Driven bymembrane potential created by primaryactive transports.

Cellular uptake and transportation by vesicles
Invagination or budding of cell membrane results in formation of vesicles.

Endocytosis

1. Contact to cell surface
2. Vesicle formation &granule release
3. Transportation

I. Canton, G. Battaglia,
Chem. Soc. Rev. 41 (2012) 2718–2739.

→ After endocytosis, materials may escape from endosome to cytosol, if needed.

Cathrin-mediated endocytosis
Firstly, materialinteract withsome receptors. clathrin
Triskelion forms “a coated pit”.

Upper limit fore f fi c i e n t
endocytois is~120 nm. But,
some cells
internalize larger
paricles (< 300nm).

Caveolae-mediated endocytosis
An invaginated pit with 50-80 nm in size ﬁnally allows forendosome formation.
Lipid ra_ (the plasma membranes of cells contain combinaXons ofglycosphingolipids and protein receptors organized in glycolipoprotein
microdomains) forms a ﬂask-shaped invaginaXon with help of caveolin.

8Other types of endocytosis
RhoA-mediated
細胞内骨格であるアクチンの制御に関わるRhoAの関与する経路。詳細は明らかでない部分が多いが、ある種のサイトカイン受容体の内在化に関連する。アクチンはエンドサ
イトーシスの機構に関わる重要な因子であるので、関連性は深いと思われる。

CDC42(cell division cycle42)-mediated
幅は< 50 nmチューブ状200-600 nm（長さ）に陥入する。
CDC42は、細胞の成長、分化、アポトーシスなどに関与し、アクチンや細胞ストレスの制御因子であるため、関係が深いものと思われる。GTP結合性。

ARF6-mediated
こちらもチューブ状に陥入する。発見から日が浅く、詳細は不明。ARF6は膜の曲率制御に関連があるとも言われる。（GTPと結合して曲率が上がり、くびれる。）

Flotilin-mediated
カベオリンと類似のコンフォメーションを持つタンパク質であるが、カベオラ型とは独立してエンドサイトーシスを起こすらしい。
9Macropinocytosis
Engulfment of a large quantity of external fluid by the formation of waving
sheet-like extensions of the plasma membrane that close, thus forming
large(> 200 nm) organelles called macropinosomes. Polymerization ofactin is a key step for engulfment.
LamellipodiaCircularlike
ruffle(葉状仮足様)Bleb
Lamellipodialike

CircularruffleBleb
Green: actin
filaments

10

Phagocytosis
Endocytosis performed by immune cells, e.g., macrophages, dendritic
cells, mast cells, neutrophils and so on. Rather large (~µm?).

For opsonized matreials(a) For IgG, recognition by Fcγ
receptor results in phagocytosis.

(b) For C3b, recognition by CR3(complement receptor 3) results inphagocytosis.

(c) Engulfment of opsonized RBC.
Actin filaments were labeled by FL
proteins.

???

???

12
M. Zhu, et al., Acc. Chem. Res. 46 (2013) 622–631. Fig. 3

particle weree coated withhad a homogeneous hydrophilic ligand shell, whereas 34-66 OT
and 66-34 OT particles had a hydrophilic–hydrophobic striatedSurface chemistry & cellular uptake- Usual cell surface is negatively charged due to glyco-chains and lipid
our particles used in thishead
study. group. => Cationic particles are favorable, but sometimes lead
Thermogravimetric⇣Potential §Ligand shell morphology/tohighcytotoxicity.
‡
analysis (%)(mV)
chemical structures- In in vivo conditions, cationic surface often induces adsorption ofproteins. (low biocompatibility）→ Suppression of non-speciﬁc uptake.
Biocompatible polymer
1538.0± 5.30 but, may
result in low cellular uptake.
HomogeneousO
Poly(ethylene“PEG
dillenma”
O Na
S
O
HS
glycol) (PEG)nO
PMPC
Poly(2-methyloxazoline) MUS
=

=

+

n

Poly(N-vinyl
pyrrolidone) (PVP)

N

N

n
O

O

n

O–

Unstructured

31.1± 0.73
structured

A. Verma and F. Stellacci

O

HS

=

randomOS

O – Na +=13
homogeneous

O

O

ace-

P

O
N+

O

O
MUS Poly(2-(methacryloyloxy)ethyl phosphorylcholine)HS

Surfacebr-OT structure

Structured

33.1± 0.64

O

=

15

HS

S

O – Na +=ynthetic
particleinteracrted theligands/
particleligandsurfacenaturaloup hasility ofd nanoze, zeta
y, and

–

MUS

O

OT

A. Verma, et al., Nat. Mater. 2008, 7, 588.

HS

to surface reconstruction

Surface of
the ARTICLE
particle
REVIEWATERIALS DOI: 10.1038/NMAT2442
Competitive binding
interactions dependon protein concentration
and body fluid composition

Characteristic
protein on/off
rates depend on
material type
and proteincharacteristics

Available surface
area, surface coverage
and angleHydrophilicof curvature
determineoradsorptionhydrophobic
profiles interactions

Crystallinity

Electronic
statesParticle
Surfacecomposition
ity
instabilHydrophobicity
wettability

wettability

Size

Charge (for example cationic binding)Chargeb

Steric hindrance
prevents binding+ + + + +
_

O.2

SH
SH

Protein conformationalchanges cause loss of
enzyme activity

e

S
S

–

_

O.2

e

S
S

Release of surface
free energy–

O2
Release of surface
free energye–h+Protein conformation,functional changes

Impact onproteinstructureand function

Proteinfibrillationh+Possible events after
Impact onproteinstructureand function

interaction withproteins.
Surface

Protein conformationalchanges cause loss of
enzyme activity

O2e–

Surfacereconstruction

Electron–holepairs leadto oxidative
damageSH
SH

Surfacereconstruction

Electron–holepairs leadto oxidative
damageSteric hindrance
prevents binding

A. E. Nel, et al., Nat. Mater. 2009, 8, 543-557.

Charge (for example cationic binding)

b

Size

HydroPossible events onparticle
surface.
phobicity
Chargee

Hydrophilicor hydrophobic
interactions

Particle
Surfacecomposition
y
it
il
b
insta

Protein binding
accelerates
dissolution ofsome materials

Available surface
area, surface coverage
and angle of curvature
determine adsorption
profilesCrystallinity

Electronic
statesBinding interactions releasesurface free energy, leading
to surface reconstruction–

Protein binding
accelerates
dissolution ofsome materialse–+ + + + +aCharacteristic
protein on/off
rates depend on
material type
and proteincharacteristics

Surface Protein conformation,
opsonization/functional changes
liganding allows
interaction
with additional
Protein nano–bio interfaces
fibrillation

Amyloid
fibre

Exposure
to cryptic
epitopes

Proteincrowding,
layering,
nucleation
Immunerecognition14

Eﬀect of Size on cellular uptake➡ Size-dependency of interaction between antibody-functionalized gold
nanoparticles (GNPs) and cells: Different internalization and signaling.
2 nm GNPs
40 nm GNPs
70 nm GNPs

Receptor

vesil
ce

核

重ね合わせ

10 nm

40 nm

W. Jiang et al. Nat.
Nanotechnol. 2008, 3, 145.
15

Eﬀect of shape on cellular uptake (1)Nano-/micro-hydrogels with various
sizes and shapes were prepared, andcellular uptake was examined.

20 µm

20 µm

dependent on the size and aspect ratios.

20 µm

20 µm

20 µm

20 µm

1 µm

1 µm

➡ Internalization into HeLa cells is

1 µm

1 µm

1 µm

J. M. DeSimone et al., PNAS, 2008, 105, 11613.

Eﬀect of shape on cellular uptake (2)Macrophages (RAW264.7)• Cervical cancer cells (HeLa)•- More ﬂat & bigger AuNP

showed higher cellular
uptake.
- Longer retenXon Xme on
the cell surface
eﬀecXvely contributes…?

K. Nambara, K. Niikura, et al.,Langmuir, 2016, 32, 12559.

Surface area/particle

Volume/particle

17

Transport from capillary
Molecular
weightLow
Molecular
WeightOrganic
chemistry

32

Oxygen180

Glucose3001,000

Low-molecularweight drug

70,00015 nm

Nano-scale 170,000
Objects
Polymer/colloid

O2

Albumin, etc

20-150 nm
tens–hundredsof nm

Viruses(Inﬂuenza, Ebola…)

7 μm

Type of transport-

Diffusion-

Protein carrier

Nano-physiology

Ig（AnXbody）

Nanomedicine

sciences

血球

Substances

Size

Red Blood Cell-

Only leaking?
Exosome-

Bleeding

参考文献『図解で学ぶDDS』(じほう)『分子薬物動態学』(南山堂)
pharmacokinetics『総合製剤学』(南山堂)
Formulation sciences『生体内薬物送達学』 (基礎生体工学講座)
橋田 充, 高倉 喜信 (著) (産業図書, 1994年)

総説

加藤将夫、杉山雄一、薬毒物のわかりやすい体内動態、中毒研究, 7, 395–403 (1994);
8, 85–97 & 163–178 (1995).

Pharmacokinetics & Physiologically based (PB) Model•For clear descripXon of the movement of drug into, through, and out of the body, we
consider the Xme course of its absorpXon, distribuXon, metabolism, excreXon, andbioavailability. （PharmacokineXcs）•Modeling by connecXng organs (as compartments) with the bloodstream (as a pipeline)=> Too complicated!!

Dose(intravenous
injecXon)

Lung
Brain
Heart
Liver

KidneyMuscleSkin
AdiposeFor each compartment, we
can set some parameters:
Kp: Xssue to bloodconcentraXon raXo
C: drug concentraXon at theorgan
V: volume of the organ
Q: Blood ﬂow rate
CL: Clearance
Bioavailability: the frac=on ofan administered dose of
unchanged drug that reaches
the systemic circula=on

Virtual Clinical Study based on “model & simulation”

杉山雄一、リバーストランスレーショナルリサーチの重要性、
YAKUGAKU ZASSHI, 137, 673-679 (2017).

杉山雄一、リバーストランスレーショナルリサーチの重要性、
YAKUGAKU ZASSHI, 137, 673-679 (2017).

22

23

, 402-406.

, 402-406.

24

Compartmental analysis
Simple models based on several compartments.
=> Useful for predicXon of drug concentraXon at any Xme.

1-compartment modela rapid intravenous injecXon (IV bolus)

X0
Tissue 2 V2V1 Tissue 1
C1

C2

Fast
Plasma Kp, Cp, Vp

C4
Tissue 4
V4

C3
Tissue 3
V3

X

C

Vd

For drugs to be eﬀecXve, they need to be able to move
rapidly from blood plasma to other body ﬂuids and Xssues.
X: Total amount of drug
Ci: drug concentration at the tissue
Vi: volume of the tissue
Ki: tissue to plasma concentration ratio = Ci/Cp(i = 1–4)“p” stands for plasma.
X = VpCp + ∑ViCi= VpCp + ∑ViKiCp= (Vp + ∑ViKi)Cp

This term should be small, if the
drug shows slow clearance.
Ideally, ViKi for the target 1ssue
should be maximized.

Vd (Distribution volume) ≡ Vp + ∑ViKi = X/Cp
kel For a single bolus IV injection
The drug concentraXon is uniform in the body compartment at all Xmesand is eliminated by a ﬁrst order process
dX/dt = –kelX(kel : elimination rate constant)
The integral of 1/x is ln(x).

X = X0·exp(–kelt)
Cp = C0·exp(–kelt)(X0 : Dose)(C0 : initial plasma concentration)

Time (t)LN of Plasma conc. (ln C)

Plasma conc. (C)Cp = C0·exp(–kelt)

C0 = X0/Vd
lnCp = lnC0 – kelt

EliminaXon half-life (t1/2):
The Xme required for theconcentraXon of the drug toreach half of its originalvalue.
t1/2 = ln(2)/kelsemi-log plot

Time (t)Plasma conc. (C)AUC (area under the curve):
The integral of the concentration-time curve (after a single dose or in steady state).

Time (t)Assignment（Due date: Nov 22nd）
1-Compartment model(for constant-rate IV infusion)
Problems）
k0: infusion ratek0
Tissue 2 V2V1 Tissue 1
C1

C2

Plasma Kp, Cp, Vp

C3
Tissue 3V3Xi) Express the total amount of drug X as afunction of t.
ii) From the equation of Cp = X/Vd, find the Cp at
the steady state using kel, k0, and Vd.
iii) Briefly describe the time course of drugconcentration in plasma.

C4
Tissue 4
V4

C

Vd
kel

Hints：- Express the mass balance regarding X using a
differential equation.
- differential of ln(x) is 1/x; integral of 1/x is ln(x);integral of 1/(ax+b) is (1/a)ln(ax+b)

1-Compartment model(for gut absorption)e.g., Single oral administration &absorbed from the gut
Xa: drug conc. in gut
ka: Absorption rate constant
F: Absorbed fraction
D: DoseD (Dose)Gut
Xa

Use the LaplacetransformFka
Cp
Tissue 2 V2V1 Tissue 1
C1

C2

Plasma Kp, Cp, Vp

C4
Tissue 4 V4C3
V3 Tissue 3

X

C

Vd
kel

LN of Plasma conc. (ln C)

Body

Cmax

gradientkel= –(gradient)28

tmax Time (t)（Appendix）Laplace transform–kaxa

2-Compartment model http://www.gatewaycoalition.org/files/hidden/deliv/ch3/3_5f.htm
O_en drug does not distribute evenly amongst all the organs. To account for this a two
compartment model is used in which drug disposiXon is biexponenXal. The drug is assumed to
distribute into a second compartment but be eliminated from the ﬁrst compartment only.
Peripheral compartment
D Central compartment(Fast distribution)(Slow distribution)(Distribution phase)
Fast distribution & elimination

dX1/dt = –(kel + k12)X1 + k21X2(Elimination phase)dX2/dt = –k21X2 + k12X1
Solved using the Laplace transform
C1 = X1/V1 = A·exp(–αt) + B·exp(–βt) (α >β)A = D(α–k21)/{V1(α–β)}
B = D(k21–β)/{V1(α–β)}V1 = D/(A + B), V2 = k12·V1/k21
Vss = V1 + V2

Slow distribution &elimination

Example of 2-compartment model
Methotrexate: Antimetabolite (antifolate type).
Used to treat cancers, autoimmune diseases etc.
Protein binding: -50%, Urine excretion：48% (1 h)Fast distribution& elimination
Slow distribution& elimination31Model-independent approach (moment analysis)

Plasma conc.

It gives us characteristic properties of drugs, but it’s not useful for predicting its
time course.
First moment
Second moment
Zero moment
Mean residence time
Variance of residence time

Time

32

Liver metabolism
Protein-bound
Drug

Drug

Interaction withblood components

Sinusoid
Endothelial cells

Membranetransport Drug

Space of Disse✓Liver metabolizes toxic compounds,
such as alcohol, drugs, etc. fordetoxification or elimination.
→ Excreted in urine or bile

Liver cell
(hepatocyte)
Internalization
Metabolitebilecapillary

Drug

Metabolite

MetaboInteraction
肝細胞内
lism
with
Protein-boundintracellular
成分との
Drug
components
相互作用

Excreted inbile『生体内薬物送達学』p. 130 を英訳- Lipophilic drugs are converted intohydrophilic compounds.
- Main route is oxidation by cytochrome P450.
(P450 has a lot of isozymes (57 types) having
many variants.)→ Drug efficacy is dependent on personal difference.

this enhanced blood exposure [149]. The impact of the saturation process depends on the extent of MPS capture of the formulation. Only
CDCs that are highly captured by Kupffer cells induce this effect [150].
CDCs designed to evade the MPS (with PEG- or other hydrophilic coat→ The materials passing throughings) do not show enhanced circulation times with increases in dosageof sinusoids(sizecan< 150
nm)
up fenestrations
to 300 mg/kg [147,148].
Two phenomena
explainthe candosebe internalizedby livertime:
cells,
unlesstheyopsonins
dependent
increment in circulation
depletionof plasma[146]
or saturation ofmacrophage
phagocytic capacity [34,151]. Kupffer
encounter
Kupffercells.
cell uptake functions can also be altered with the administration of→ Main internalization pathway is pinocytosis.
CDCs containing cytotoxic drugs that have a deleterious effect on theThen, bile
excretion occurs.
macrophages[152].

Bile excretion/Gallbladder

Bile: bile is produced by the liver, andstored and concentrated in the gallbladder.
After eating, the stored bile is discharged
into the duodenum for the digestion of lipids
in the small intestine. Main component ofgallbladder bile is bile salts and fats(cholesterol, fatty acids, and lecithin), which→ Bile excretion is the only elimination path of can work as an emulsifier.
5.3.non-biodegradable
Targeted delivery to the livermaterials with size > 6 nm.
Cationic materials show higher uptake.
Hepatocytes are functional units responsible for most of the metaBut,
excretion
process
is very(< 48nm)
h for
Liver
bolic
and secretory
activitiesof the liver.
Smallslow
CDCs (b150that
5-10% of dose).
Pinocytosys

Space of Disse

Hepatocyte
Gallbladder（胆嚢）bile capillary

Duodenum(十二指腸)

（Advanced contents）Organ clearance
outinCapillary

Cout

Plasma protein

Qi

Capillary

Flow rate
Endothelial cells

Protein-binding

Interstitial fluid

CB = Cin
drug

CLint,iElimination
enzymes

Intrinsic clearance

CLint,ivel
Organ clearance-

Eorg,i = (QiCin – QiCout,i)/QiCin

CB: Drug conc. in the artery
Elimination rate at organ i vel,i:Eorg,i-

Organ extraction ratio Eorg,i:CLorg,ivel,i = CLorg,i·CB= QiCin – QiCout,i= Eorg,iQiCin
From CB = Cin
CLorg,i = Eorg,i·Qi
1 – Eorg,i ≡ Forg,i

F: Availability
Both Organ extraction ratio & avialabilry can be determined
only by organ clearance CLorg,i & Blood flow rate Qi.
Upper limit of the E value is 1. Therefore, the upper limit of CLorg,ican be determined by the upper limit value of Qi. (Particularly for
rapid elimination cases.)35

（Advanced contents）Drug distribution to blood cells
Hct: Hematocrit(Volume ratio of red blood cells to
the total volume of blood）
1 – Hct

Hct

PlasmaPlasma (55%) Cp
White blood cells &platelet (< 1%)

Free drug

Free drug

PlasmaproteinProteins ofRBC

RBC (45%) C
RBC
Protein-bounddrug
Drug cocn. in blood cell components (Rb)

Rb = CB/Cp (BC distribution ratio)
CB = (1 – Hct)Cp + HctCRBC
Therefore,
Rb = CB/Cp = (1 – Hct) + HctCRBC/Cp
In the case of CRBC = 0, Rb = 1 – Hct

Red blood cells (RBC)

36

Protein-bounddrug

You do not need to consider the
RBC distribution, when you use
drug carriers or water soluble drug.
36Model system for evaluation of PK
As an alternative for animal experiments.
Ex.1) To estimate liver clearance, microsomes prepared from human liver cells areused. （細胞を破砕してできる小胞体が細分化した小胞で、肝細胞由来だと代謝酵素であるシトクロム
P450を含む）

Ex.2) To estimate intestinal absorption behavior, Caco-2 cell layer system is often used.
(to evaluate drug permeation, function of transporter, etc…)
X.-W. Yang, et al.
Journal of Chinese
Integrative Medicine:Volume 5, 2007, p. 637.

TranswellCaco-2 cells
Microvilli
Semipermeable
membraneDrug passing throughthe epithelial cell layer

Drug absorption mechanism
at intenstinal epithelia.
消化管粘膜部位での薬物吸収機構

MucosaTight junction

transporter

Application of microﬂuidic devices as a model system
K. Sato, et al., ANALYTICAL SCIENCES, 2012, 28, 197–199.
- PDMS-based(シリコンゴム) microfluidic

device（1.5 mm-wide）-

GI tract model system + liver metabolism
model
Final target: breast cancer by systemic
circulation
Useful for estimation of PK/PD

Model system for GI tract!38

Pharmacodynamics (PD)
Pharmacodynamics (PD) is the study of how a drug affects an organism, whereas
pharmacokinetics (PK) is the study of how the organism affects the drug. PD places
particular emphasis on dose–response relationships, that is, the relationships
between drug concentration and effect.
Conc.

Target tissue

Admin.

Distribution

EffectiveConc.

Pharmacological
EffectDrug
Absorp.
Blood
Conc.

Elimin.

Drug-binding to receptor
or target site.
Dose

Drug conc. in plasma

Response – Time

Conc. – Time
Oral Admin.

Time

Response

Concentration

Sigmoidal

PK/PD

Metabolism/Excretion
Dose

Drug Response

Blood

Response

PK/PD解析の目的：

Time

薬効発現に関わる生物学的なプロセス込みでの速度論的考察を可能にし、最も安全かつ有効な薬物・剤形、投与計画の設計につなげる。

Eﬀect compartment model
Sometimes, drug response isdelayed.
Drug Response

Eﬀect compartment
Eﬀect/
response
Drug conc. in plasma
Pharmacology
Drug conc. in plasma＊各コンパートメントは１次の速度論で結合され、薬効コンパートメン
トの分布容積は小さく、全体の濃度変化に影響を与えないと仮定。

Drug conc. in plasma
x-axis：DelayedDrug conc. in plasma

x-axis：Fall in blood pressure(%)

Fall in blood pressure(%)

Drug conc. in plasma

Drug conc. in theeffect compartment

Bunazosin：an alpha 1 antagonist.
Bunazosin was initially developed
to treat benign prostatic
hyperplasia (BPH).

LinearDrug conc. in effectcompartment!40