Arquivo
Metabolismo e eliminação de drogas
Dúvidas
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Site
www.gilbertodenucci.com
Aula
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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
● Pilocarpine Solution
○ Pilocarpine ointment
▲Fluorometholone Solution
∆ Fluorometholone Oitment
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig. 9.36
Scanning electron micrographs showing the crystal habit of (a) Form 1 and
(b) Form 2 of paracetamol grown from supersaturated IMS
a
b
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig. 1.11
Comparison of serum levels obtained with suspensions of chloramphenicol
palmitate after oral administration of a dose equivalent to 1.5g of
chloramphenicol
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig. 1.13
Serum Levels obtained after oral administration of suspension containing 250mg
ampicilin as the anhydrate and as the trihydrate
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig. 1.14
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
Plasma (black) and breast milk (gray) concentrations of bupropion after 100-mg oral
doses every 6hr
Milk/plasma
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 14.21
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 12.11
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
An example of quantitiative
whole body autoradiography
(QWBA) in rat after
administration of C-14labeled 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
Drug Metabolism in drug design and development – Wiley Interscience – Fig 9.2
Consequências do Metabolismo de Medicamentos
1 – Diminuição da ativade farmacológica
2 – Aumento da atividade farmacológica
3 – Aumento da toxicidade (carcinogênese, mutagênese,
citotoxicidade)
4 – Alteração da atividade farmacológica
Foye’s Principles of Medicinal Chemistry – Chapter 8 – pag. 202
Reação de Biotransformação e Farmacológica
do metabólito ativo - I
Reação
Exemplo
Droga ativa para Metabólito Inativo
Anfetamina
Deaminação
Fenilacetona
Fenobarbital
Hidroxilação
Hidroxifenobarbital
Droga ativa para Metabólito Ativo
Desmetilação
Morfina
Procainamida
Acetilação
Morfina
Fenilbutazona
Hidroxilação
Codeína
Oxifenilbutazona
Reação de Biotransformação e Farmacológica
do metabólito ativo - II
Reação
Exemplo
Droga inativa para Metabólito Ativo
Hidrólise
Hetacilina
Azoredução
Sulfasalazina
Ampicilina
Sulfapiridina+àcido
5 amino salicílico
Droga ativa para Intermediário Reativo
Acetaminofeno
Hidroxilação
Benzopireno
Hidroxilação
aromática
aromática
Intermediário reativo
(necrose hepática)
Intermediário reativo
(carcinogênico)
Percent of clinically important drugs metabolized by
human CYP450 isoforms
2E1
4%
3A4/5
36%
2D6
21%
1A1
3%
1A2
8%
2B6
3%
2C8/9
17%
2C18/19
8%
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
Polymorphic Distribution
Number of Subjects
• A trait that has differential expression in >1% of the population
PM
EM
Increasing Metabolic Capacity
URM
Examples of biotransformation reactions leading to a
preferred marketed drug
Drug Metabolism in drug design and development – Wiley Interscience – Fig 1.1
Examples of biotransformation reactions leading to a
preferred marketed drug
Desloratadine
Drug Metabolism in drug design and development – Wiley Interscience – Fig 1.1
Examples of biotransformation reactions leading to a
preferred marketed drug
Drug Metabolism in drug design and development – Wiley Interscience – Fig 1.1
Examples of biotransformation reactions leading to a
preferred marketed drug
Drug Metabolism in drug design and development – Wiley Interscience – Fig 1.1
(a) Fractions of drug metabolized by various
enzyme systems
(a) Fractions of drug that are P450 substrates
metabolized by individual P450s
Drug Metabolism in drug design and development – Wiley Interscience – Fig 2.1
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
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 13.1
The plateau plasma concentration of nortriptyline varies widely in 263 patients receiving a regime
of 25 mg nortriptyline orally 3 times daily
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 12.2
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 13.2
The daily dose of warfarin required to produced a similar degree of anticoagulation in 200 adult
patients varies widely
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 12.1
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
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 12.4
Genetic plays a significant role in the maintenance dose requirement of warfarin used in the
treatment of various cardiovascular diseases
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 13.4
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 13.3
The bimodal distribution of the 6-hr plasma isoniazid concentration in 483 subjects after 9.8 mg/kg
isoniazid orally results from acetylation polymorphism
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 13.6
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
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 20.2
Enoxacin inhibits theophylline elimination
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 17.6
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 17.7
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
Tempo de
Protrombina (sec)
Concentração de
Warfarina (mg/L)
Efeito de um indutor de metabolismo (Rifampicina 600mg/dia
por 3 dias) na administração de warfarina (1.5 mg/kg)
20
10
4
Dose única
2
1
40
30
20
Rifampicina
14
12
Faixa Normal
0
2
4
6
Dias
8
10
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
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 17.17
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 17.18
Warfarin-phenylbutazone
interaction
Concentração de clozoxaona (mg/L)
Efeito da administração do dissulfiram no
metabolismo da clorzoxazona
100
Após dissulfiram
(500mg v.o. 10h antes)
10
1
Antes dissulfiram
0.1
0
3
6
9
12
Horas
Clin. Pharmacol, 1993
Concentração de Alprenolol (mg/L)
Indução causada pelo pentobarbital
0.1
Oral antes
0.01
Oral depois
i.v. antes
i.v. depois
0.001
0
2
4
6
Horas
8
10
Clin. Pharmacol. Ther., 1977
Efeito da cimetidina (400mg 6/6h 4d) na
biodisponibilidade do labetolol
% de alteração
80
AUC
Oral I.V.
CL
F
60
40
20
0
-20
N.S.
J. Clin. Pharmacol, 1984
Impact of Route of Administration of Diltiazem on the Extent of inhibition
of Oral Lovastatin
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Table 17.6
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 17.10
Cilastatin markedly increases the urinary excretion of the antibiotic impenem by
inhibiting the dehydropeptidase in the kidney responsible for its metabolism
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 17.12
Clarithomycin irreversibly inactivates CYP3A, the enzyme responsible for the
metabolism of midazolam
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 17.12
Rifampin, administered intravenously, increases the systemic exposure of orally
administered atorvastatin, and shortens its half-life.
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 17.19
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 (●).
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 17.23
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 20.3
1200
1000
500
R-mefenitoína
T ½ = 76h
100
50
S- mefenitoína
T ½ = 2.13h
10
0
A
2
4
6
8
10
12
Tempo (dias)
Concentração Plasmática (mg/mL)
Concentração Plasmática (mg/mL)
Alteração da hidroxilação de enantiômeros da mefenitoína
14
1200
1000
500
R- mefenitoína
100
50
S- mefenitoína
10
0
B
2
4
6
8
10
12
Tempo (dias)
14
Subjects received morphine sulfate orally (11.7 mg, colored lines) and intravenously (5
mg, black lines) on separate occasions.
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 20.7
Two situation following constant-rate drug infusion are depicted
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 20.8
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 20.9
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)
Drug Metabolism in drug design and development – Wiley Interscience – Fig 3.2
Common SULT substrate. Arrows indicate site of sulfonation for each
Drug Metabolism in drug design and development – Wiley Interscience – Fig 3.6
Examples of CYP substrates and inhibitors used in clinical DDI studies
Drug Metabolism in drug design and development – Wiley Interscience – Table 5.4
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 13-1
Some Genetic Polymorphisms in Pharmacodynamics
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Table 13-2
MEDICAMENTOS QUE SÃO METABOLIZADOS POR ISOFORMAS DO CITOCROMO P450
1A2
2B6
Clozapina
Bupropiona
Ciclobenzaprina
Ciclofosfamida
Efavirez
Metadona
Imipramina
Naproxeno
Teofilina
2C8
2C19
Inibidores de
Bomba de
Próton:
Omeprazole
Lansoprazole
Pantoprazole
Rabeprazole
2C9
AINEs:
Diclofenaco
Ibuprofeno
Piroxicam
Ciclofosfamida
Progesterona
2E1
Betabloqueadores:
S-metoprolol
Timolol
Paracetamol
Etanol
Antidepressivos:
Hipoglicemiantes orais:
Tolbutamida
Glipizida
Anti-epilépticos:
Diazepam
Fenitoína
Fenobarbital
Amitriptilina
Clomipramina
2D6
Antagonistas de Angiotensina II:
Irbesartan
Losartan
Amitriptilina
Clomipramina
Desipramina
Imipramina
Paroxetina
3A4,5,7
Antibióticos macrolídeos:
Claritromicina, eritromicina,
Anti-arrítmico:
Quinidina
Benzodiazepínicos:
alprazolam, diazepam, midazolam,
triazolam
Imunomoduladores:
Ciclosporina, Tacrolimus
Antipsicóticos:
Celecoxib
Fluvastatina
Naproxeno
Fenitoína
Sulfametoxazole
Tamoxifeno
Tolbutamida
Warfarina
Haloperidol
Risperidona
Codeína
Dextrometorfano
Flecainida
Ondansetrona
Tamoxifeno
Tramadol
Venlafaxina
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
Bisórpma
Gleevec,
Haloperidol
Metadona,
Quinina
Sildenafil
Tamoxifeno
Vincristina
INIBIDORES DE CITOCROMO P450
1A2
Cimetidina
Fluoroquinolonas
Fluvoxamina
Ticlopidina
2B6
Ticlopidina
2C8
Gemfibrozila
Montelukast
2C19
Fluoxetina
Fluvoxamina
Cetoconazol
Lansoprazol
Omeprazol
Ticlopidina
2C9
Amiodarona
Fluconazol
Isoniazida
2D6
2E1
Amiodarona
Disulfiram
Bupropriona
Clorfeniramina
Cimetidina
Clomipramina
Fluoxetina
Haloperidol
Metadona
Paroxetina
Quinidina
Ritonavir
3A4,5,7
Inbidores de
Protease:
Indinavir
Nelfinavir
Ritonavir
Amiodarone
Cimetidina
Claritromicina
Diltiazem
Eritromicina
Fluvoxamina
Itraconazol
Cetoconazol
Verapamil
INDUTORES DE CITOCROMO P450
1A2
2B6
Tabaco
Fenobarbital
Fenitoína
Rifampicina
2C8
2C19
2C9
2D6
2E1
3A4,5,7
Rifampicina
N/A
Etanol
Isoniazida
Carbamazepina
Fenobarbital
Fenitoína
Secobarbital
Rifabutina
Rifampicina
Hypericum perfuratum
Troglitazona
Changes in the activity of CYP3A4 per milligram of protein in the duodenum of pediatric
patients as a function of their age
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 14.12
Half-life od diazepam is shortest in the infant and logest in the newborn and the aged
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 14.14
Creatinine clearances of neonates on Day 1 and Day 6 after birth
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 14.8
Creatinine clearance, corrected (colored circles) and uncorrected (open circles) for body
surface area, plotted versus conceptional age
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 14.9
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).
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 14.11
The plateau plasma drug concentrations of two antiepileptic drugs, carvamazepine (A)
and valproic acid (B). Are measured after chronic oral medication in children
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 14.22
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 14.16
The minimum alveolar concentration (%) of desflurane required for general anesthesia
varies with age
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 14.5
Comparison of the Pharmacokinetics of Selected Drugs in Healthy Subjects with that in Patients
with Hepatic Cirrhosis
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Table 15.1
Child-Pugh Score for Assessing the Prognosis of Chronic Liver Disease (Mainly Cirrhosis)
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Table 15.2
Relationship between amprenavir AUC and the Child-Pugh score
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 15.2
Activities of the conjugating enzymes, glucuronyltransferase, sultransferase,
acetyltransferaase, and glutathione transferase in normal (black) and abnormal (colored)
human livers vary widely
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 15.3
50
40
30
20
10
0
Cirrose
102
56
Clerance do clordiazepóxico (ml/min/kg)
Meia-vida (h) do clordiazepóxido
Normal
Normal
2.2 o
Cirrose
1.0
0.8
0.6
0.4
0.2
0.0
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
Blood
46.3 ± 18.4
1.3
90.7 ± 25.7
2.0
Brain
3.33 ± 0.6a
27.0
CSF
23.3 ± 11.2
ND
43.8 ± 14.6
75.6 ± 27.4
15.2 ± 3.55
60.9 ± 17.9
“Sections had > 40%
of pixels below quantification limit (BQL).
4.2
Testes
(+/+)
112 ± 40.6
13.2
3.3
(-/-)
Ratio
147 ± 8.3
5.4 ± 2.4
146 ± 17.1
58.1 ± 6.8
4.0
37.8 ± 5.47
2.1
117 ± 5.47
NV
160 ± 25.7
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.
Muscle
33.0 ± 9.09
1.5
70.4 ± 20.2
179 ± 52.6
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
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
Bremazocine
1.50 ± 0.21
κ
44.1 ± 5.5
66.3 ± 3.8***
Deltophin II
δ
0.166 ± 0.037
Methadone
µ
41.7 ± 5.8
109 ± 17***
Naltrindole
4.44 ± 0.93
δ
12.5 ± 2.4
55.4 ± 5.1a
SNC 121
δ
17.0 ± 1.8
147 ± 15a
1.34 ± 0.25
0.263 ± 0.010 **
1.58 ± 0.36
2.61 ± 0.55
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
8.60 ±
1.26
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
P-gp
at individual time10.4
points±1.9
is reported in
Loperamide
µ in Vbrain between mdr1a(/)
9.86
±deficient
1.73 and wild-type
103 mice
± 6***
Fig. 1.
C. Dagenais et al. / Biochemical Pharmacology 67 (2004) 269–276 – table 1
Compound
Substratos para Glicoproteína P
Amiodarona
Clorpromazina
Claritromicina
Ciclosporina
Daunorubicina
Dexametasona
Digoxina
Diltiazem
Eritromicina
Estradiol
Etoposide
Felodipina
Fexofenadina
Flufenazina
Hidrocortisona
Itraconazol
Cetoconazol
Lidocaína
Loperamide
Lovastatina
Mifepristona
Nelfinavir
Nicardipina
Nifedipina
Ondansetron
Paclitaxel
Progesterona
Prometazina
Quinidina
Reserpina
Ritonavir
Saquinavir
Sirolimus
Tacrolimus
Tamoxifen
Taniposide
Testosterona
Trifluoperazina
Verapamil
Vinblastina
Vincristina
Indutores e Inibidores de Glicoproteína P
Indutores
Rifampicina
Ritonavir
Hypericum perforatum
Iohimbina
Inibidores
Amiodarona
Atorvastatina
Clorpromazina
Claritromicina
Ciclosporina
Diltiazem
Eritromicina
Felodipina
Flufenazina
Hidrocortisona
Indinavir
Itraconazol
Cetoconazol
Lidocaína
Mifepristona
Nelfinavir
Nicardipina
Nifedipina
Progesterona
Propranolol
Quinidina
Reserpina
Ritonavir
Saquinavir
Tacrolimus
Tamoxifeno
Testosterona
Trifluoperazina
Verapamil
24
Estudo em dose
única
20
Suco de Toronja
16
Água
12
8
4
0
0
2
4
6
8 10 14
Horas após a Dose
Pressão Arterial Sentado
(min Hg)
Efeito do suco de toronja na farmacocinética e
farmacodinâmica da Felodipina
150
140
130
120
110
80
70
60
0
2
4
6
8 23 24
Horas após a Dose
Concentração do Indinavir (μg/mL)
Efeito do Hypericum perforatum na farmacocinética do
Indinavir
14
Administrado após
Hypericum perforatum
12
10
8
6
4
2
0
0
1
2
Hora (h)
3
4
5
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)
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 12.10
Cyclosporine inhibits the elimination of rosuvastatin, a drug primarily excreted
unchanged in bile and urine
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 17.11
Concetration (nmol/mL)
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
Elderly
5
Healthy
0
0
4
8
12
16
20
24
28
Time (hours)
Applied – Biopharmaceutics & Pharmacokinetics – fig.
Felodipina (5mg) via oral
Idade
67-79
20-34
Palpitação
Rubor
Clearance
3/11
9/11
248 mL/h
1/12
1/12
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).
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 16.4
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 20.11
Concentração Plasmática Salicilamida
(mg/L)
Concentração plasmática de salicilamida após várias
administração por via oral em distintas doses
30
2.5
20
2.0
10
1.0
0.5
0
0
100
200
300
Minutos
Typical Pharmacokinetics Parameters of Digoxin in the Absence and
Presence of Quinidine
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Table 17.7
Saturable First-Pass Metabolism of Nicardipine Observed at Steady State
Following oral Doses of 10 to 40 mg Every 8Hr
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Table 16.2
????????????????????????????????
Applied Clinical Pharmacokinetics – Larry Bauer – Eq; pag 19
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
Applied Clinical Pharmacokinetics – Larry Bauer – Fig. 3-4
Relationship between creatinine clearance and digoxin clearance to estimate initial digoxin
clearance when no drug concentrations are available
Applied Clinical Pharmacokinetics – Larry Bauer – Fig. 3-3
Relação entre os valores de CL/F da fenitoína e idade
em pacientes controles
Controles
25
CL/F (ml h-1 kg-1)
20
15
10
5
0
20
25
30
35
40
45
Idade (anos)
50
( ) 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.
Relação entre os valores de CL/F da fenitoína e idade
em pacientes controles
CL/F (ml h-1 kg-1)
25
Controles
20
15
10
5
0
2
4
6
8
( )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
Influence of aging on serum phenytoin concentrations: a pharmacokinetic analysis based on therapeutic drug monitoring data – Epilepsy Research 59 (2004) 155-165.
Relação entre os valores de CL/F da fenitoína e idade
em pacientes idosos
Idosos
25
CL/F (ml h-1 kg-1)
20
15
10
5
0
Idade (anos)
65
70
75
80
85
90
( ) 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.
Relação entre os valores de CL/F da fenitoína e dose
em pacientes idosos
Idosos
CL/F (ml h-1 kg-1)
25
20
15
10
5
0
2
4
6
8
( ) 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
Influence of aging on serum phenytoin concentrations: a pharmacokinetic analysis based on therapeutic drug monitoring data – Epilepsy Research 59 (2004) 155-165.
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)
Applied Clinical Pharmacokinetics – Larry Bauer – Fig. 4.1
Schematic representation of a hemodialysis system in which drug is
passively transferred across a semipermeable mambrane (---) from blood
to dialysate
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 15.16
Concentration-time graph for tombramycin in a hemodialysis patients using estimated population
pharmacokinetics parameters
Applied Clinical Pharmacokinetics – Larry Bauer – Fig. 3-14
Fenobarbital em paciente renal terminal
de 70kg
Vu= 77L
Clu = -.4 L/h
k= 0.005/hr
t1/2 = 137 h
Plasma dialysis clearance and unbound dialysis clearance with an adjustment for
molecular size for 27 different drugs show considerable variability
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 15.17
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
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 15.18
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 15.21
Relationship between systemic bioavailability (mean ± SD of five patients) and dwell time when
teicoplanin is administered intraperioneally
Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 15.22
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.
Prova Medicina Unicamp 2010 – Turma A
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.