arquivo metabolismo e eliminação de drogas dúvidas [email protected] site aula...

Arquivo Metabolismo e eliminação de drogas

Dúvidas

[email protected]

Site

www.gilbertodenucci.com

Aula

[email protected]

Arquivo Metabolismo e eliminação de drogas

Dúvidas

[email protected]

Site

www.gilbertodenucci.com

Aula

[email protected]

Questão 01 – Valor = 1,0 pontos

A- Descreva o gráfico acima (note que o coeficiente de lipossolubilidade foi corrigido pelo peso molecular). B- Explique a razão da correção mencionada acima C- Interprete o gráfico em relação aos medicamentos com quadrados pretos D- Ofereça uma explicação para o resultado obtido com a fenitoína (phenytoin).

Aqueous humour levels after dosing with pilocarpine and fluorometholone in ointment and aqueous solution

Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig. 9.36

● Pilocarpine Solution○ Pilocarpine ointment▲Fluorometholone Solution∆ Fluorometholone Oitment


Scanning electron micrographs showing the crystal habit of (a) Form 1 and (b) Form 2 of paracetamol grown from supersaturated IMS

a b


Comparison of serum levels obtained with suspensions of chloramphenicol palmitate after oral administration of a dose equivalent to 1.5g of

chloramphenicol


Serum Levels obtained after oral administration of suspension containing 250mg ampicilin as the anhydrate and as the trihydrate

Galantamine pharmacokinetics in dogs given intranasal formulation (filled diamonds), oral solution (filled triangles), and oral tablet (filled squares). The data are shown for galantamine measured in (A)

plasma; (B) the CSF; and (C) as the ratio of drug measured in CSF to plasma

Proteins and Peptides Phamacokinetic, Pharmacodynamic and Metabolic Outcomes – Pag. 176 – Fig. 1

Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 14.21

Plasma (black) and breast milk (gray) concentrations of bupropion after 100-mg oral doses every 6hr

Milk/plasma

Mean AUC, maximum Plasma Concentration, and Terminal Half-life of Erythropoietin in End-Stage Renal Desease Patients followig Intravenous

and Subcutaneous Administration

Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Table 21.15

Drug Metabolism in drug design and development – Wiley Interscience – Fig 9.2

An example of quantitiative whole body autoradiography

(QWBA) in rat after administration of C-14-

labeled material. The figure shows the distribuition of

radioactivity at various time points postdose. The image was generated by taking a

sliced section of the whole body of rat and exposing it to

a phosphorimaging film

Foye’s Principles of Medicinal Chemistry – Chapter 8 – pag. 202

1 – Diminuição da ativade farmacológica

2 – Aumento da atividade farmacológica

3 – Aumento da toxicidade (carcinogênese, mutagênese, citotoxicidade)

4 – Alteração da atividade farmacológica

Consequências do Metabolismo de Medicamentos

Reação de Biotransformação e Farmacológica Reação de Biotransformação e Farmacológica do metabólito ativo - Ido metabólito ativo - I

Anfetamina

Fenobarbital

Anfetamina

Fenobarbital

Reação Exemplo

Droga ativa para Metabólito Inativo

Deaminação

Hidroxilação

Deaminação

Hidroxilação

Fenilacetona

Hidroxifenobarbital

Fenilacetona

Hidroxifenobarbital

Codeína

Procainamida

Fenilbutazona

Codeína

Procainamida

Fenilbutazona

Droga ativa para Metabólito AtivoDroga ativa para Metabólito Ativo

Desmetilação

Acetilação

Hidroxilação

Desmetilação

Acetilação

Hidroxilação

Morfina

Morfina

Oxifenilbutazona

Morfina

Morfina

Oxifenilbutazona

Reação de Biotransformação e Farmacológica Reação de Biotransformação e Farmacológica do metabólito ativo - IIdo metabólito ativo - II

Hetacilina

Sulfasalazina

Hetacilina

Sulfasalazina

Reação Exemplo

Droga inativa para Metabólito Ativo

Hidrólise

Azoredução

Hidrólise

Azoredução

AmpicilinaSulfapiridina+àcido 5 amino salicílico

AmpicilinaSulfapiridina+àcido 5 amino salicílico

Acetaminofeno

Benzopireno

Acetaminofeno

Benzopireno

Droga ativa para Intermediário ReativoDroga ativa para Intermediário Reativo

Hidroxilação

aromática

Hidroxilação

aromática

Hidroxilação

aromática

Hidroxilação

aromática

Intermediário reativo (necrose hepática)

Intermediário reativo (carcinogênico)

Intermediário reativo (necrose hepática)

Intermediário reativo (carcinogênico)

3A4/536%

2E14%

2D621%

2C18/198%

2C8/917%

2B63%

1A28%

1A13%

Percent of clinically important drugs metabolized by human CYP450 isoforms

Isoformas de citocromo P450

• CYP 1A2

• CYP3A

• CYP2C9

• CYP2C19

• CYP2D6

Nomenclatura do citocromo CYP2D6

• CYP –citocromo P450

• 2 - família genética

• D – subfamília genética

• 6 – gene específico

PM EM URMIncreasing Metabolic Capacity

Num

ber

of S

ubje

cts

• A trait that has differential expression in >1% of the population

Polymorphic Distribution

Examples of biotransformation reactions leading to a preferred marketed drug




Desloratadine

(a) Fractions of drug metabolized by various enzyme systems

(a) Fractions of drug that are P450 substrates metabolized by individual P450s



The much smaller intrapair variability in plateau plasma concentration of nortriptyline between nine identical twins than between 12fraternal twins indicates that genetics plays a major role in

nortriptyline pharmacokinetics


The plateau plasma concentration of nortriptyline varies widely in 263 patients receiving a regime of 25 mg nortriptyline orally 3 times daily


The daily dose of warfarin required to produced a similar degree of anticoagulation in 200 adult patients varies widely


There is considerable interindividual pharmacodynamics variability in response to oral anticoagulant warfarin as demonstrated by the substantial spread in the unbound concentration of

the active S-isomer associated with a similar degree of anticoagulation in a group of 97 patients on maintenance tehrapy


Genetic plays a significant role in the maintenance dose requirement of warfarin used in the treatment of various cardiovascular diseases


The bimodal distribution of the 6-hr plasma isoniazid concentration in 483 subjects after 9.8 mg/kg isoniazid orally results from acetylation polymorphism

Displayed semilogatithmically are the plasma concentrations of methylprednisolone (●) and its water-soluble hemisuccinate ester (●) following an i.v. bolus injection of 80 mg of

the ester; mean of 11 subjects


Enoxacin inhibits theophylline elimination


Citocromo P4503A

• Responsável pelo metabolismo de:• Maioria dos bloqueadores de canais de cálcio• Maioria dos benzodiazepínicos• Maioria dos inibidores de protease do HIV• Maioria das estatinas• Ciclosporina• Maioria dos anti-histamínicos não sedativos• Presente no TGI e fígado

Inibidores de CYP3A

• Cetoconazole

• Fluconazole

• Itraconazole

• Cimetidina

• Claritromicina

• Eritromicina

• Suco de toronja

Arritmia ventricular (Torsades de Pointes) devido a associação de medicamentos

• Mulher de 39 anos• Terfenadina 60mg 2x/dia e cefaclor 250mg 3x/dia• Auto-medicação com cetoconazol 200mg 2x/dia para

candidíase vaginal• Palpitações, síncope, torsades de pointes (QTc 655 msec)

Indutores de CYP3A

• Carbamazepina

• Rifampicina

• Rifabutina

• Ritonavir

• Hypericum perforatum

Faixa Normal

20

10

4

2

4030201412

0 2 4 6 8 10

1

Tem

po d

e P

rotr

ombi

na (

sec)

Con

cent

raçã

o de

W

arfa

rina

(m

g/L

)

Dias

Efeito de um indutor de metabolismo (Rifampicina 600mg/dia por 3 dias) na administração de warfarina (1.5 mg/kg)

Dose única

Rifampicina

O'Reilly RA. Interaction of sodium warfarin and rifampin. Studies in man. Ann Intern Med. 1974 Sep;81(3):337-40.

Administration of phenobarbital (60 mg daily) to a patient receiving dicumarol chronically (75 mg daily) reduce, through induction, the plasma concentration of the

anticoagulant (●) and prothrombin time (○), a measure of its effect on the concentration of the vitamin Kl-dependent clotting factors. The time course of the events is largely

controlled by the kinetics of phenobarbital, half-life 4 days


Warfarin-phenylbutazone interaction

Clin

ical

Pha

rmac

okin

etic

s an

d Ph

arm

acod

ynam

ics

– C

once

pts

and

App

licat

ions

– F

ourt

h E

ditio

n –

Fig.

17.

18

Con

cen

traç

ão d

e cl

ozox

aon

a (

mg/

L)

Horas

100

10

1

0.10 3 6 9 12

Efeito da administração do dissulfiram no metabolismo da clorzoxazona

Após dissulfiram (500mg v.o. 10h antes)

Antes dissulfiram

Clin. Pharmacol, 1993

0.1

0.01

0.0010 2 4 6 8 10

Indução causada pelo pentobarbital

Horas

Con

cen

traç

ão d

e A

lpre

nol

ol (

mg/

L)

Oral depois

i.v. antes i.v. depois

Oral antes

Clin. Pharmacol. Ther., 1977

80

60

40

20

0

-20

% d

e al

tera

ção

AUC CL FOral I.V.

N.S.

Efeito da cimetidina (400mg 6/6h 4d) na biodisponibilidade do labetolol

J. Clin. Pharmacol, 1984

Impact of Route of Administration of Diltiazem on the Extent of inhibition of Oral Lovastatin


Cilastatin markedly increases the urinary excretion of the antibiotic impenem by inhibiting the dehydropeptidase in the kidney responsible for its metabolism


Clarithomycin irreversibly inactivates CYP3A, the enzyme responsible for the metabolism of midazolam


Rifampin, administered intravenously, increases the systemic exposure of orally administered atorvastatin, and shortens its half-life.


Plasma concentration vs. time profiles of halofantrine (a) and N-desbutylhalofantrine (b) upon oral administration of a single dose of 500 mg halofantrine hydrochloride alone (■) or together with 50

mg fluconazole (▲) to 15 adult male volunteers. The data are the means ± SD

Effect of fluconazole on the pharmacokinetics of halofantrine in healthy volunteers - Journal of Clinical Pharmacy and Therapeutics (2009) 34, 677–682 – Fig 1

Mean plasma concentration of desipramine after a 50-mg oral dose given alone (●) and after 8 daily doses (60 mg each) of fluoxetine (●).


Alteração da hidroxilação de enantiômeros da mefenitoína

0 2 4 6 8 10 12 140 2 4 6 8 10 12 140 2 4 6 8 10 12 140 2 4 6 8 10 12 14

1200

1000

500

100

50

10

1200

1000

500

100

50

10

1200

1000

500

100

50

10

1200

1000

500

100

50

10Con

cen

traç

ão P

lasm

átic

a (

g/m

L)

Con

cen

traç

ão P

lasm

átic

a (

g/m

L)

Con

cen

traç

ão P

lasm

átic

a (

g/m

L)

Con

cen

traç

ão P

lasm

átic

a (

g/m

L)

Tempo (dias)Tempo (dias) Tempo (dias)Tempo (dias)

R-mefenitoínaR-mefenitoína

S- mefenitoínaS- mefenitoína

R- mefenitoínaR- mefenitoína

S- mefenitoínaS- mefenitoínaT ½ = 2.13hT ½ = 2.13h

T ½ = 76hT ½ = 76h

AA BB

Subjects received morphine sulfate orally (11.7 mg, colored lines) and intravenously (5 mg, black lines) on separate occasions.


Two situation following constant-rate drug infusion are depicted


Classification of human P450s based on major substrate class

Drug Metabolism in drug design and development – Wiley Interscience – Table 2.1

Localization of UGT enzymes in the endoplasmic reticulum.

The active site is located on the inside of the ER with a single transmembrane domain and a 25 a.a. COO - cytosolic tail. UDPGA is transported into the ER and is trans-stimulated by UDPGlcNAC. Once the glucuronides are formed, they must be transported out of the ER by a separate transport protein (depicted by flipping through the membrane)


Common SULT substrate. Arrows indicate site of sulfonation for each


Examples of CYP substrates and inhibitors used in clinical DDI studies

Drug Metabolism in drug design and development – Wiley Interscience – Table 5.4

Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Table 13-1

Frequency of Genetic Polymorphisms Producing Slow Metabolism in Some Drug-Metabolizing Enzymes and Representative Substrates

Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Table 13-2

Some Genetic Polymorphisms in Pharmacodynamics

MEDICAMENTOS QUE SÃO METABOLIZADOS POR ISOFORMAS DO CITOCROMO P450

1A2 2B6 2C8 2C19 2C9 2D6 2E1 3A4,5,7

ClozapinaCiclobenzaprinaImipraminaNaproxenoTeofilina

BupropionaCiclofosfamidaEfavirezMetadona

Inibidores de Bomba de Próton:OmeprazoleLansoprazolePantoprazoleRabeprazole

Anti-epilépticos:

DiazepamFenitoínaFenobarbital AmitriptilinaClomipraminaCiclofosfamidaProgesterona

AINEs:DiclofenacoIbuprofenoPiroxicam

Hipoglicemiantes orais:TolbutamidaGlipizida

Antagonistas de Angiotensina II:IrbesartanLosartan

CelecoxibFluvastatina Naproxeno

FenitoínaSulfametoxazoleTamoxifenoTolbutamidaWarfarina

Betabloqueadores:S-metoprololTimolol

Antidepressivos:

AmitriptilinaClomipraminaDesipraminaImipraminaParoxetina

Antipsicóticos:

HaloperidolRisperidona

Codeína DextrometorfanoFlecainidaOndansetronaTamoxifeno

TramadolVenlafaxina

ParacetamolEtanol

Antibióticos macrolídeos:Claritromicina, eritromicina,

Anti-arrítmico:Quinidina

Benzodiazepínicos:alprazolam, diazepam, midazolam,triazolam

Imunomoduladores:Ciclosporina, Tacrolimus

HIV inibidores de protease:indinavir, ritonavir, saquinavir

Anti-histamínicos:astemizole, clorfeniramina

Bloqueadores de canais de cãlcio:amlodipina, diltiazem, felodipina,nifedipina, nisoldipina, nitrendipina,verapamil

Estatinas:atorvastatina, cerivastatina, lovastatina

BisórpmaGleevec,Haloperidol Metadona, QuininaSildenafilTamoxifenoVincristina

INIBIDORES DE CITOCROMO P450

1A2 2B6 2C8 2C19 2C9 2D6 2E1 3A4,5,7

CimetidinaFluoroquinolonas

FluvoxaminaTiclopidina

Ticlopidina GemfibrozilaMontelukast

FluoxetinaFluvoxaminaCetoconazolLansoprazolOmeprazolTiclopidina

AmiodaronaFluconazolIsoniazida

Amiodarona

BuproprionaClorfeniraminaCimetidina

ClomipraminaFluoxetinaHaloperidolMetadonaParoxetinaQuinidinaRitonavir

Disulfiram Inbidores de Protease:IndinavirNelfinavirRitonavir

AmiodaroneCimetidinaClaritromicinaDiltiazemEritromicina

FluvoxaminaItraconazolCetoconazolVerapamil

INDUTORES DE CITOCROMO P450

1A2 2B6 2C8 2C19 2C9 2D6 2E1 3A4,5,7

Tabaco FenobarbitalFenitoínaRifampicina

RifampicinaSecobarbital

N/A EtanolIsoniazida

CarbamazepinaFenobarbitalFenitoínaRifabutinaRifampicinaHypericum perfuratum Troglitazona


Changes in the activity of CYP3A4 per milligram of protein in the duodenum of pediatric patients as a function of their age


Half-life od diazepam is shortest in the infant and logest in the newborn and the aged


Creatinine clearances of neonates on Day 1 and Day 6 after birth


Creatinine clearance, corrected (colored circles) and uncorrected (open circles) for body surface area, plotted versus conceptional age


Mean changes in CYP2D6 (A) and CYP3A4 (B) activity (relative to adult values during the first year after birth, with both in vitro enzyme activity and liver weight taken into

account).


The plateau plasma drug concentrations of two antiepileptic drugs, carvamazepine (A) and valproic acid (B). Are measured after chronic oral medication in children


The minimum alveolar concentration (%) of desflurane required for general anesthesia varies with age


Comparison of the Pharmacokinetics of Selected Drugs in Healthy Subjects with that in Patients with Hepatic Cirrhosis


Child-Pugh Score for Assessing the Prognosis of Chronic Liver Disease (Mainly Cirrhosis)


Relationship between amprenavir AUC and the Child-Pugh score


Activities of the conjugating enzymes, glucuronyltransferase, sultransferase, acetyltransferaase, and glutathione transferase in normal (black) and abnormal (colored)

human livers vary widely

50

40

30

20

10

0

1.0

0.8

0.6

0.4

0.2

0.0

Normal Cirrose Normal Cirrose 102

562.2 o

Mei

a-vi

da (

h) d

o cl

ordi

azep

óxid

o

Cle

ranc

e do

clo

rdia

zepó

xico

(m

l/m

in/k

g)

Clin. Pharmacol, 1979

Comparação esquemática entre um capilar cerebral e um capilar periférico (Kandel et al., 2000).

Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases

W. Lo¨scher, H. Potschka / Progress in Neurobiology 76 (2005) 22–76

Características da Barreira Hemato-Encefálica

Targeted nanoparticles for drug delivery through the blood–brain barrier for Alzheimer’s disease

C. Roney et al. / Journal of Controlled Release 108 (2005) 193–214

Localização esquemática das proteínas responsáveis por efluxo de medicamentos nas células endoteliais dos

capilares cerebrais responsáveis pela barreira hemato-encefálica

Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases

W. Lo¨scher, H. Potschka / Progress in Neurobiology 76 (2005) 22–76

Mecanismos de Transporte na Barreira Hemato-Encefálica

Targeted nanoparticles for drug delivery through the blood–brain barrier for Alzheimer’s disease

C. Roney et al. / Journal of Controlled Release 108 (2005) 193–214

Concentrations (nCig) of [14C]-Amprenavir in CD-1 Mice Pretreated with GF120918 and in FVB mdr la/lb Double Knockout Mice

GF120918 chemical knockout mdr 1a/1b genetic double knockout

Tissue Vehicle GF120918 Ratio (+/+) (-/-) Ratio

Blood 46.3 ± 18.4 90.7 ± 25.7 2.0 112 ± 40.6 147 ± 8.3 1.3

Brain 3.33 ± 0.6a 43.8 ± 14.6 13.2 5.4 ± 2.4 146 ± 17.1 27.0

CSF 23.3 ± 11.2 75.6 ± 27.4 3.3 58.1 ± 6.8 NV ND

Testes 15.2 ± 3.55 60.9 ± 17.9 4.0 37.8 ± 5.47 160 ± 25.7 4.2

Muscle 33.0 ± 9.09 70.4 ± 20.2 2.1 117 ± 5.47 179 ± 52.6 1.5

Note: Data are the average from 3-4 animals ± the standard deviation. NV = Not visible. ND = not determined. Limit of Quantitation (LOQ): 2.447 nCi/g.

“Sections had > 40% of pixels below quantification limit (BQL).

Pharmaceutical Research, Vol. 16 No 8,1999

The effect of elacridar (GF120918) on the oral bioavailability of topotecan.

Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs TRENDS in Pharmacological Sciences Vol.27 No.1 January 2006

Initial brain uptake clearances (Clup, mL·100g-1 ·min-1)of opioids during in situ perfusion in mice

Compound Opioid receptor subtype

Wild-type mice

P-gp deficient mice

P-gp effect

Meperidine µ 185 ± 38 180 ± 33 0.98 ± 0.27

Fentanyl µ 184 ± 24 228 ± 9* 1.24 ± 0.27

Morphine µ 1.04 ± 0.03 1.29 ± 0.08** 1.24 ± 0.08

U-69593 κ 39.2 ± 3.0 52.6 ± 8.8a 1.34 ± 0.25

Bremazocine κ 44.1 ± 5.5 66.3 ± 3.8*** 1.50 ± 0.21

Deltophin II δ 0.166 ± 0.037 0.263 ± 0.010 ** 1.58 ± 0.36

Methadone µ 41.7 ± 5.8 109 ± 17*** 2.61 ± 0.55

Naltrindole δ 12.5 ± 2.4 55.4 ± 5.1a 4.44 ± 0.93

SNC 121 δ 17.0 ± 1.8 147 ± 15a 8.60 ± 1.26

Loperamide µ 9.86 ± 1.73 103 ± 6*** 10.4 ±1.9

DPDPE δ 0.0547 ± 0.0293 0.636 ± 0.067 *** 11.6 ± 6.4

P-gp effect is defined as the ratio between Clup in mdr1a(/) P-gp deficient and wild-type mice. Data are presented as mean SD of four individual experiments at a single time point or from multiple time point experiments (N ¼ 4 per point at three time points) *P < 0:05; **P < 0:01; ***P < 0:001. aStatistical significance of differences in Vbrain between mdr1a(/) P-gp deficient and wild-type mice at individual time points is reported in Fig. 1.

C. D

ag

en

ais

et

al. /

Bio

chem

ical Ph

arm

aco

log

y 6

7 (

20

04

) 2

69

–27

6 –

tab

le 1

Substratos para Glicoproteína P

AmiodaronaClorpromazina ClaritromicinaCiclosporinaDaunorubicina DexametasonaDigoxinaDiltiazemEritromicina

EstradiolEtoposideFelodipinaFexofenadinaFlufenazinaHidrocortisonaItraconazolCetoconazolLidocaínaLoperamideLovastatinaMifepristonaNelfinavirNicardipinaNifedipina

OndansetronPaclitaxelProgesteronaPrometazinaQuinidinaReserpinaRitonavirSaquinavirSirolimusTacrolimusTamoxifenTaniposideTestosteronaTrifluoperazinaVerapamilVinblastinaVincristina

Indutores e Inibidores de Glicoproteína P

Indutores Inibidores

RifampicinaRitonavirHypericum perforatumIohimbina

AmiodaronaAtorvastatinaClorpromazinaClaritromicinaCiclosporinaDiltiazemEritromicinaFelodipinaFlufenazinaHidrocortisonaIndinavirItraconazolCetoconazolLidocaínaMifepristona

NelfinavirNicardipinaNifedipinaProgesteronaPropranololQuinidinaReserpinaRitonavirSaquinavirTacrolimusTamoxifenoTestosteronaTrifluoperazinaVerapamil

0 2 4 6 8 10 14

Horas após a Dose

Con

cent

raçã

o F

elod

ipin

a (n

mol

/L)

Suco de Toronja

Água

Estudo em dose única

0 2 4 6 8 23 24

24

20

16

12

8

4

0

150

140

130

120

11080

70

60

Horas após a DoseP

ress

ão A

rter

ial S

enta

do

(min

Hg)

Efeito do suco de toronja na farmacocinética e farmacodinâmica da Felodipina

0 1 2 3 4 5

14

12

10

8

6

4

2

0

Hora (h)

Con

cent

raçã

o do

Ind

inav

ir (

μg/m

L)

Administrado após Hypericum perforatum

Efeito do Hypericum perforatum na farmacocinética do Indinavir


A. Mean plasma concentrations with time of midazolam and (B) fexofenadine following a single oral dose of 4-mg midazolam and 180-mg fexofenadine, respectively, alone (control, black) and

after 11-day treatment with 300-mg St. John’s wort 3 times daily (colored)

Cyclosporine inhibits the elimination of rosuvastatin, a drug primarily excreted unchanged in bile and urine


Applied – Biopharmaceutics & Pharmacokinetics – fig. 20.2

Plasma concentrations (mean ± SD) of felodipine after an oral dose during steady-state treatment with 5mg twice daily in healthy subjects

(n = 12) and elderly hypertensive patients (n = 11)

15

10

5

00 4 8 12 16 20 24 28

Time (hours)

Con

cetr

atio

n (n

mol

/mL

)

Healthy

Elderly

Felodipina (5mg) via oral

Idade 67-79 20-34

Palpitação 3/11 1/12

Rubor 9/11 1/12

Clearance 248 mL/h 619 mL/h

Plasma concentration, normalized to dose, as a function of time following the oral administration of two tablets (●) and four tablets (●) of ultramicronized grinseofulvin

(125 mg/tablet).


Concentração plasmática de salicilamida após várias Concentração plasmática de salicilamida após várias administração por via oral em distintas doses administração por via oral em distintas doses

3030

2020

1010

00

3030

2020

1010

0000 100 100 200 200 300 30000 100 100 200 200 300 300

2.52.52.52.5

2.02.02.02.0

1.01.01.01.00.50.50.50.5

Con

cen

traç

ão P

lasm

átic

a S

alic

ilam

ida

(mg/

L)

Con

cen

traç

ão P

lasm

átic

a S

alic

ilam

ida

(mg/

L)

MinutosMinutos

Typical Pharmacokinetics Parameters of Digoxin in the Absence and Presence of Quinidine


Saturable First-Pass Metabolism of Nicardipine Observed at Steady State Following oral Doses of 10 to 40 mg Every 8Hr


Applied Clinical Pharmacokinetics – Larry Bauer – Eq; pag 19

????????????????????????????????

Applied Clinical Pharmacokinetics – Larry Bauer – Fig. 3-4

Relationship between creatinine creatinine clearance and aminoglycoside elimination rate constant (ke) to estimate initial aminoglycoside elimination when no drug concentrations are available. The

y-axis intercept (0.014h-1) is nonrenal elimination for aminoglycosides


Relationship between creatinine clearance and digoxin clearance to estimate initial digoxin clearance when no drug concentrations are available

25

20

15

10

5

020 25 30 35 40 45 50

Idade (anos)

CL

/F (

ml h

-1 k

g-1)

Controles

Relação entre os valores de CL/F da fenitoína e idade em pacientes controles

( ) pacientes em monoterapia e ( ) pacientes com terapia adicional de fenobarbital. The equations of the lines were CL/F = 32.3 – 0.25 x age (r = -0.28, P < 0.05) for elderly patients and CL/F = 1.39 – 0.02 x age (r = -0.05, NS) for controls. For results of analysis on comedication subgroups, see Section 3.3.

Influence of aging on serum phenytoin concentrations: a pharmacokinetic analysis based on therapeutic drug monitoring data – Epilepsy Research 59 (2004) 155-165.

2 4 6 8

25

20

15

10

5

0

CL

/F (

ml h

-1 k

g-1)

Dose (mg kg-1 day-1)

Controles

Relação entre os valores de CL/F da fenitoína e idade em pacientes controles

( )patients on phenytoin monotherapy and ( ) patients comedicates with phenobarbital. The equations of the lines were CL/F = 15.0 – 0.09 x dose (r = -0.02, NS) for elderly patients and CL/F = 12.2 + 0.16 x dose (r = -0.04, NS) for controls


65 70 75 80 85 90

25

20

15

10

5

0

CL

/F (

ml h

-1 k

g-1)

Idosos

Relação entre os valores de CL/F da fenitoína e idade em pacientes idosos

( ) pacientes em monoterapia e ( ) pacientes com terapia adicional de fenobarbital. The equations of the lines were CL/F = 32.3 – 0.25 x age (r = -0.28, P < 0.05) for elderly patients and CL/F = 1.39 – 0.02 x age (r = -0.05, NS) for controls. For results of analysis on comedication subgroups, see Section 3.3.

Idade (anos)


2 4 6 8

25

20

15

10

5

0

CL

/F (

ml h

-1 k

g-1)

Dose (mg kg-1 day-1)

Idosos

Relação entre os valores de CL/F da fenitoína e dose em pacientes idosos

( ) pacientes em monoterapia e ( ) pacientes com terapia adicional de fenobarbital. The equations of the lines were CL/F = 15.0 – 0.09 x dose (r = -0.02, NS) for elderly patients and CL/F = 12.2 + 0.16 x dose (r = -0.04, NS) for controls


Applied Clinical Pharmacokinetics – Larry Bauer – Fig. 4.1

Concentration-time plot for gentamicin 120 mg given as a ½-hour infusion (squares with solid line) and as a 1-hour infusion (circles with dashed line)


Schematic representation of a hemodialysis system in which drug is passively transferred across a semipermeable mambrane (---) from blood

to dialysate


Concentration-time graph for tombramycin in a hemodialysis patients using estimated population pharmacokinetics parameters

Fenobarbital em paciente renal terminal de 70kgVu= 77L

Clu = -.4 L/hk= 0.005/hrt1/2 = 137 h


Plasma dialysis clearance and unbound dialysis clearance with an adjustment for molecular size for 27 different drugs show considerable variability


Displayed is the fraction of drug in the body at the start of dialysis that is eliminated by 3 hr of dialysis treatment a function of unbound clearance (nodialysis elimination) and unbound volume of

distribution


Relationship between systemic bioavailability (mean ± SD of five patients) and dwell time when teicoplanin is administered intraperioneally

Prova Medicina Unicamp 2010 – Turma A

The first step in the conversion of the retroviral agent abacavir (ABC) to its active metabolite, carbovir triphosphate, is phosphorylation to ABC monophosphate by adenosine phosphotransferase.

a . Proponha um esquema terapêutico para o paciente.

b . Justifique.

Amiodarone is an antiarrhythmic with predominantly class III (Vaughan ± William's classification) effects [1]. The major metabolite of amiodarone, N-desethylamiodarone (N-DEA), has been identified in humans as a consequence of hepatic and possibly intestinal mucosa N-dealkylation [2±4].

a. Descreva os gráficos utilizando parâmetros farmacocinéticos.

b. Proponha uma explicação para o resultado observado.

c. Proponha uma investigação para confirmar sua hipótese .

d. Estime as potenciais consequências farmacodinâmicas, justificando-as em função de conceitos farmacocinéticos.

Prova Medicina Unicamp 2010 – Turma A

However, dramatic reduction in half-life during dialysis does not

guarantee that the procedure effectively removes drug during a single-

sialysis treatment. Take, for example, phenobarbital in a 70-kg end-stage

renal disease patient whose pharmacokinetic parameters are Vu = 77 L,

Clu = 0.4 L/hr, k = 0.005 hr-1, and t1/2 = 137 hr. Using a value of 150

mL/min (9 L/hr) for unbound dialysis clearance the half-life of

phenobarbital is reduced to 5.7 hr during dialysis.

arquivo metabolismo e eliminação de drogas dúvidas [email protected] site aula...

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