2013 fall 5th class pk 약물남용, 사이버마약

Drug Abuse – 5환경 및 약물남용 -5

Pharmacokinetic (PK) aspect of Drugs약물 동력학

Chungnam Natl. Univ.Dept. of Forensic Sciences

충남대 과학수사학과

Aug. – Dec., 2013

최성운 Sungwoon Choi

1

Drug Metabolism – quick review

Two phases of metabolism: 2종의 대사

Phase I 일 (1)상 대사

Parent compound reacts to introduce or 모체화합물에 expose a functional group 관능기를 넣거나 노출 시킨다 Phase II 이상 (2) 대사

Parent compound of phase I metabolite is covalently modified

(conjugated) to an endogenous reactant 일상대사 산물을 내인성 물질과 접합

Usually enzyme catalyzed processes 효소촉매과정

Liver is the primary site of both phase I and II metabolism 간은 1,2상 대사의 중심

View on Metabolism 체내 약독물에 대한 대사를 일상과 이상으로 나누어 자세히 설명하시오

Commons.wikimedia.org

Drug Metabolism – chemistry of phase I metabolism 1 상 대사

Oxidation 산화a) Aromatic( 방향족 ) and Aliphatic( 지방족 ) hydroxylation (very common) 방향족 , 지방족의 수산화 – 매우 흔함

More on Metabolism

HN

NEt2O

Me

Me HN

NEt2O

Me

Me

OHCLogP = 1.9536 CLogP = 1.2366

Lignocaine

HN

HNO

O

O

Me

Me

Et

CLogP = 1.712

HN

HNO

O

O

Me

Me

EtOH

CLogP = -0.495

Pentobarbitone

Lidocaine – Local Anesthetic, Antiarrhythmatic 국소마취 , 부정맥치료제

Short-Acting Barbiturate 장시작용 바르비탈류 3

Drug Metabolism – chemistry of phase I metabolism 일상대사의 화학

Oxidation 산화b) Dealkylation (very common) 탈알킬화 ( 탈 탄화수소화 ) methamphetamine 에서 amphetamine 생성

View on Metabolism

N

NO

Cl N

NO

Cl

OH

N

HN

O

Cl

HCOH

CLogP = 3.1704CLogP = 3.02076

Diazepam

O

O

HO

NMe

MeO

O

HO

NMe

HO HO

O

HO

NMe

Codeine Morphine

CLogP = 1.5365 CLogP = 1.1307

HCOH

4

Drug Metabolism – chemistry of phase I metabolism

Oxidationc) Oxidative deamination (CYP450s and Monoamine oxidase) 산화적 탈아민

d) N-Oxidation - 합성 진통제 메페리딘

View on Metabolism

NH2HO NH2 O

Amphetamine

CLogP = 1.742

CLogP = 1.43

N

Me

O

O

N

O

O

Me O-

Meperidine

5


Oxidatione) S-Oxidation 황산화

f) Alcohol / Aldehyde oxidation

Metabolism

N

S

N

Cl

CLogP = 5.7996

N

S

N

Cl

O

CLogP = 3.72306

Chloropromazine

OH

Ethanol

H

O

OH

O

Typical Antipsychotic 항정신약

6

약물 - 운전영향F.T. 에 중요

Metabolism

Caffeine CocaineMDMA

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Reductions 환원 g) Nitro-reduction 니트로 화합물의 환원

h) Other

View on Metabolism

O2NHN

O

Cl

Cl

OH OH

CLogP = 1.283

Chloramphenicol

NHN

O

Cl

Cl

OH OH

O

H2NHN

O

Cl

Cl

OH OH

CLogP = 0.313

8


Hydrolysis 가수분해 - cocaine, heroin 등 a) Esters

b) Amides 아마이드결합 분해

View on Metabolism

Me

N

OO OH

Me

N

OO OH

O O HO O

CLogP = 2.7729CLogP = 3.7539

Vasotec ACE inhibitor

HN

O

NH

NH2 HO

O

NH

+

Lidocaine metabolite

HN

O

N

Lidocaine 9

Oxidation, Reduction & Hydrolysis 관여 효소

OxidationCytochrome P450 monooxygenase systemFlavin-containing monooxygenase systemAlcohol dehydrogenase & aldehyde dehydrogenaseMonoamine oxidaseCo-oxidation by peroxidase

ReductionNADPH-cytochrome P450 reductaseReduced(ferrous) cytochrome P450 reductase

HydrolysisEsterases & AmidasesEpoxide hydrolase

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Other phase I reactions – less common

Ring cyclization

N-carboxylation

Transamidation

Isomerization

Decarboxylation

View on Metabolism

11

Drug Metabolism – chemistry of phase II metabolism 2상 대사

Catalyzed by a family of enzymes called transferases 전달효소 집단 에 의해 촉매Two substrate reactions (i.e. the parent compound or phase I metabolite and an endogenous molecule) 두가지 기질반응 모체화합물 /일상 대사물 + 내인성 분자Except for acylation and methylation, the endogenous molecules are highly polar 내인성 물질은 극성이 매우 높다

Transferases are found in Liver, but also kidney, lung, skin, gastrointestinal tract and brain 온몸에 퍼져있다 간을 주요장기로 신장 , 폐 , 피부 , 위장관 등에 Resulting conjugates are primarily eliminated by renal excretion 접합물 -주로 신장배설

View on Metabolism

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Drug Metabolism – chemistry of phase II metabolism

Glucuronidation 포합 - 글루쿠론화

View on Metabolism

N

NH

O

OO

OHHO

OP

OP

O

-O OO-O

O

HO

HOHO

HO

UDP-glucose

UDPG-dehydrogenase

2NAD+ 2NADH

N

NH

O

OO

OHHO

OP

OP

O

-O OO-O

O

HO

HOHO

HO

O

UDP-glucuronic acid

UDP-glucuronosyltransferase

R-OH

N

NH

O

OO

OHHO

OP

OP

O

-O OO-O

H

O

HO

HOHO

HO

O

OR

UDP Inversion ofstereochemistry

phosphorylase

O

HO

HOHO

HO

O

OPO3H

glucose-1-phosphate

PhenolAlcoholCarboxylic acidAminesAmidesThiols

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Sulfate conjugation 황산포합

View on Metabolism

NO

OHHO

OP

OP

O

-O OO-O

PhenolAlcoholAminesAmidesThiols

N

N

N

H2N

P-O

O-O

ATP

ATP-sulfutylase

SO4-2 N

O

OHHO

OP

OS

-O

-O OOO

N

N

N

H2N

+ PPi

ATP

ADP

APS kinase

NO

OHO

OP

OS

-O

-O OOO

N

N

N

H2N

P-O

-OO

PAPS

sulfotransferase

R-OHR-OSO3-

NO

OHO

OP

-O

-O O

N

N

N

H2N

P-O

-OO

3'-phosphoadenosine-

5'-phosphate

APS

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Methylation

By S-adenosylmethionine(SAM) / methyl transferase SAM / Catechol O-methyl transferase (COMT)

R-OH to R-OCH3 Also amines, imidazoles, thiols are substrates

Acylation

Glutathione conjugation 독성대사물질제거에 중요

View on Metabolism

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Toxicity – linked to metabolism

Toxicity related to xenobiotic oxidation

Finally, Toxicity

O

ClR

Acyl chloride

Would be eliminated as a lead!!!

O2NHN

O

Cl

Cl

OH OH

Chloramphenicol

O2

CYP450

NADPH O2NHN

O

Cl

Cl

OH OH

OHO2N

HN

O

Cl

O

OH OH

HCl

Acyl chloride

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Would you eliminate this lead? - 땅콩버터에 서식하는 곰팡이 – 아플라 톡신

Naturally occurring mycotoxin from a fungus, highly carcinogenic substance

Finally, Toxicity

O

O

Epoxide


O

O

O

O O

OH

HO

O

O

O O

OH

HO

O

O

O O

OH

HOH

NN

NHN

H2N

O

Aflatoxin B1 Epoxide Potent hepato-carcinogen

O DNAO2

CYP450

NADPH

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Finally, Toxicity


Acetaminophen

O2

CYP450

NADPH

O

O

Michael acceptor

OH

NH

O

OH

N

O

OH

H2O O

N

O

Would eliminate this lead?

Liver Toxicity

Michael acceptor

AcetaminophenPain & Fever 진통 , 해열Therapeutic dose – little, no toxicityRapid metabolism - excretedAt high dose – normal level of enzyme depleted, additional route- Reactive metabolites – liver toxicity

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Quick review on Drug Metabolism and Toxicity 대사와 독성

More on Toxicity-Drug Metabolism

Drug Stablemetabolite

phase I

water solubility up

phase IIconjugatedadduct

water solubility up

detoxication pathway

Excretion

Bioactivation

(Toxic) Electrophilic,Reactive metabolites

CYPsnon-CYPs

Liver, Lung, Kidney, Skin

MacromoleculesCovalent Bonding

Altered Cellular Function

Cell Death, Tissue Necrosis, Carcinogenicity, Teratogenicity, Immune-mediated Toxicities etc.

Reactive metabolites

How to avoid them?

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제독 경로

독성대사물생성 경로

Biotransformation …cont.

Biotransformation sites – widely distributed throughout the body 온몸에 분포 대사 장소 간이 주요장기 liver is the primary organ – large size, high conc. of enzyme 크기 , 효소농도 --- primary subcellular components – microsomes (small vesicles) of the endoplasmic reticulum 간 - 마이크로좀 주요장소 & the soluble fraction of the cytoplasm( 세포질 ) microsomal enzyme – most of Phase I and glucuronidation enzyme cytosolic enzyme – generally Phase II 2 상대사 most important enzyme system in Phase I: cytochrome P-450 enzyme system or MFO (mixed function oxidase) responsible for oxidation 산화대사 책임 / 주임무 Kidney & lungs – 10 to 30% of liver’s capacity Skin, intestines, testes & placenta

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Biotransformation 대사영향요소 … cont.

Modifiers of Biotransformation – relative effectiveness of metabolism 대사 변경 요인 – 대사효과에 상대적 효과1) Species – well known, the basis for selective toxicity 종간차이 ex.) malathion in mammal – hydrolysis to relatively safe metabolites but in insects – oxidized to malaoxon, lethal to insects 곤충에 치명적 pharmaceuticals – use Lab. Animals – basically comparable with some exceptions2) Age – human fetuses( 태아 ) & neonates (newborns) – limited metabolic abilities in the aged – metabolism decreased 노령 – 대사 감소 adolescents – fluctuate, early adulthood – stabilized 연령차이

MalathionOrganophosphateIrreversible cholinesterase inhibitorHead lice/mosquito

MalaoxonMore toxic

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Biotransformation …cont.

Modifiers of Biotransformation – relative effectiveness of metabolism

3) Gender – hormone-related differences 성별차이 4) Genetic variability – ex.) Phase II acetylation reaction – “slow metabolizers” (inactivators), specific genetic-related defects 유전차이5) Poor Nutrition – deficiencies can decrease the ability to synthesize metabolizing enzyme 영양상태 차이 – 체내 효소 합성 감소6) Enzyme inhibition/Induction – prior exposure to certain chemicals 선 노출 inhibition/enhanced capability of specific enzymes 특정 효소 Enzyme inducers: alcohol, isoniazid, phenobarbital etc. 효소유도 / 억제7) Dose Level 용량차이 the amount of drug exceeds(after saturation) the specific enzyme capacity level of parent toxin build up and/or 특정 대사효소 포화 may enter a different metabolic pathway 효소의 양 - 제한적 – 다른 대사경로 ex.) acetaminophen – normal dose, 96% to non-toxic metabolites only ~ 4% oxidized to toxic metabolite – this conjugated with glutathione to excretion 글루타치온 포합 but with 7-10 times dose – more to toxic metabolites 효소포화 후배설 – glutathione depletion( 고갈 ) – liver toxicity( 간독성 ) 약독물 ( 마약류 ) 대사에 영향을 미치는 요인을 들고 설명하시오

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Drug Affect different people differently. – Why?

Known Factors – quick review 약독물의 사람들에 대한 효과 차이 마약류의 효과가 사람마다 다르게 나타나게 하는 요인을 설명하시오Age – decreased amounts of liver metabolizing enzymes (after 30s) 30 이후 감소 older vs. younger person 연령차이 - 간 대사 효소량 차이Ethnicity – varying levels of specific metabolizing enzymes 종족간 차이 Asian (low level of alcohol metabolizing enzyme) vs. EuropeanHeredity – genetic, fast or slow drug-specific metabolism 유전 1/12 – lacks CYP450-2D6 enzyme – “sudden death syndrome” 급사 증후 from MDMA (Ecstasy)Sex – male vs. female – different rates of metabolizing drugs 성별차이Health – healthier – better tolerance to a drug (liver disease-less metabolism)Allergy – certain people – allergies to certain drug 특정 약물에 대한 알러지Psychiatric state – people with mental illness (chemical imbalance) 정신병자 뇌 내 신경 전달 물질의 불균형 / 불안정 severe effects from smaller amounts of hallucinogens 소량의 환각제에 심각한 효과 Combined drug use – cross-react each other (drug-drug interaction) enzyme inducer 약물 상호작용 – 효소 증강등 23

Distribution – disposition model

Disposition: the term often used to integrate all the processes of distribution , biotransformation, & eliminationDisposition model: to describe how a toxicant moves within the body with time (known as kinetic model), named for the number of areas of the body (known as compartments) that the chemical may go, blood, fat (adipose tissue), bone, liver, kidney are major compartments.One compartment open model: distributed instantaneously & evenly in the body , & eliminated at a rate & amount that is proportional to the amount left in the body – “first-order” rate, only few chemicals follow this

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Distribution – disposition model …cont.

Two compartment open model: for most chemicals distributed first compartment in the body (usually blood), then distributed to another compartment from which can be eliminated and/or return to the first compartment half-life: “biological half-life”, most commonly used – 이해필요 1/t = …

Multiple compartment model: several peripheral body compartments a chemical may go, including long-term storage, metabolism & elimination may not that simple.

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Excretion 배설

Elimination: very important in determining the potential toxicity 주요독성결정인자 if eliminated rapidly, less likely able to concentrate in & damage critical cells 빨리 배설시 주요 세포내 농도 / 손상 낮음 제거 / 배설Same chemical & physical properties govern – absorption as described before to be eliminated from the body 흡수관련 물리화학성질 – 배설에도 관련

Routes: urine, feces, & exhaled air 뇨 , 변 , 호기 - urinary system( 비뇨기 ), GI system( 위장관 ), respiratory system( 호흡기 )

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Excretion 배설 … cont.

Urinary Excretion: Kidney, nephron 뇨배설 - 신장 , 네프론 Filtration – large pores, 40A (10-10m) in the glomerular capillaries( 신 모세혈관 ) 여과 큰 구멍 / 세공 존재 M.W. larger than 60,000 can’t pass through 큰 분자량 - 통과 불가 bound form with plasma protein also, only free form 자유형태 만 Secretion 분비 , 배출 ? Reabsorption: pH of the urine 재흡수 – 뇨의 산 / 알칼리 도 --- 마약류 재흡수 if the urine is alkaline – weak acids are ionized( 이온화 ), excreted( 배설 ) ---- acidic – weak acids are less ionized 낮게 이온화 – undergo reabsorption 재흡수 됨

27

Fecal Excretion 변배설

Two processes 두경로1) Excretion in bile 담즙 , then enters the intestine: relatively slow process important route for compds. with slow metabolism, urinary, biliary excretion2) Direct excretion into the lumen of GI tract 위장관 으로 직접 배출

Biliary route involves active secretion via specific transport system 특정 전달기로 배설 comparatively large, ionized molecules (large M.W. conjugates, >300) 비교적 크고 이온화 된 분자Enterohepatic circulation 장간순환 – 배설후 효소 분해 – 유리 – 장 재흡수

Enzymes in the intestinal flora ( 장내 세균 )Hydrolyzing – glucuronide, sulfate conjugatesRelease less polar compds. - reabsorbed

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Excretion …cont.

Exhaled Air – important route of excretion for xenobiotics(metabolites) 호기 that exist in a gaseous phase in the blood 혈액내 개스상 존재물의 주요 배설 경로 blood gases – passive diffusion( 확산 ) into the alveolus 폐포 with a low solubility( 낮은용해도 ) – more rapidly eliminated 더빨리 배출 / 제거 volatile liquids – readily excreted via the expired air 술은 ? 휘발성 액체 proportional( 비례 ) to its vapor pressure 증기압 술 ( 에탄올 ), 본드 , 기타 용매Other route of excretion 다른배설경로 - 모유 , 땀 , 침 , 눈물 , 정액 mother’s milk(acidic, pH=6.8, 3-4% lipids): DDT, lead, polybrominated sweat, saliva, tears, semen biphenyls

29

CNS Drugs – Blood-Brain Barrier (BBB) 혈액뇌관문 Quick review on BBB

Tight junctions between capillary endothelial cells 모세혈관 내부세포의 밀착Composed of occludin, claudin, junction adhesion molecule proteins 여러 특정 단백질로 구성Express high level of active efflux transport proteins 방출펌프 단백질 대량존재 P-glycoprotein (P-gp), Multidrug Resistance Protein-1 (MRP-1), Breast

Cancer Resistance Protein (BCRP)

P-gp: known as ATP-binding cassette 170 kDa plasma membrane protein Energy-dependent drug efflux pump Verapamil is a chemical inhibitor Exact Mechanism is unknown

Final challenge with BBB - CNS 작용 마약류

30

Some pictures on P-gp

images from Google

Final challenge with BBB

31

Modifications required for optimal BBB penetration 뇌혈액 관문 통과에 필요한 변형

“Rule of 5” (For Oral Drugs 경구 )

< 5 Log P < 500 Molecular Weight < 5 H-bonding donor < 5 H-bonding acceptor

To 마약류?

< 4 Log P < 400 Molecular Weight 60 – 100 Å Polar Surface Area

Final challenge with BBB

journals.prous.com

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Review, Q & A

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Documents

2013 fall 5th class pk 약물남용, 사이버마약