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Arquivo Metabolismo e eliminação de drogas Dúvidas Site Aula Arquivo Metabolismo.

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Apresentação em tema: "Arquivo Metabolismo e eliminação de drogas Dúvidas Site Aula Arquivo Metabolismo."— Transcrição da apresentação:

1 Arquivo Metabolismo e eliminação de drogas Dúvidas Site Aula Arquivo Metabolismo e eliminação de drogas Dúvidas Site Aula

2 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).

3 Aqueous humour levels after dosing with pilocarpine and fluorometholone in ointment and aqueous solution Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig Pilocarpine Solution Pilocarpine ointment Fluorometholone Solution Fluorometholone Oitment

4 Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig Scanning electron micrographs showing the crystal habit of (a) Form 1 and (b) Form 2 of paracetamol grown from supersaturated IMS ab

5 Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig Comparison of serum levels obtained with suspensions of chloramphenicol palmitate after oral administration of a dose equivalent to 1.5g of chloramphenicol

6 Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig Serum Levels obtained after oral administration of suspension containing 250mg ampicilin as the anhydrate and as the trihydrate

7 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

8 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig Plasma (black) and breast milk (gray) concentrations of bupropion after 100-mg oral doses every 6hr Milk/plasma

9 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig

10 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

11 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

12 Foyes Principles of Medicinal Chemistry – Chapter 8 – pag – 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

13 Reação de Biotransformação e Farmacológica do metabólito ativo - I Anfetamina Fenobarbital Anfetamina Fenobarbital ReaçãoExemplo Droga ativa para Metabólito Inativo Deaminação Hidroxilação Deaminação Hidroxilação Fenilacetona Hidroxifenobarbital Fenilacetona Hidroxifenobarbital Codeína Procainamida Fenilbutazona Codeína Procainamida Fenilbutazona Droga ativa para Metabólito Ativo Desmetilação Acetilação Hidroxilação Desmetilação Acetilação Hidroxilação Morfina Oxifenilbutazona Morfina Oxifenilbutazona

14 Reação de Biotransformação e Farmacológica do metabólito ativo - II Hetacilina Sulfasalazina Hetacilina Sulfasalazina ReaçãoExemplo Droga inativa para Metabólito Ativo Hidrólise Azoredução Hidrólise Azoredução Ampicilina Sulfapiridina+àcido 5 amino salicílico Ampicilina Sulfapiridina+àcido 5 amino salicílico Acetaminofeno Benzopireno Acetaminofeno Benzopireno Droga 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)

15 Percent of clinically important drugs metabolized by human CYP450 isoforms

16 Isoformas de citocromo P450 CYP 1A2 CYP3A CYP2C9 CYP2C19 CYP2D6

17 Nomenclatura do citocromo CYP2D6 CYP –citocromo P família genética D – subfamília genética 6 – gene específico

18

19 PMEMURM Increasing Metabolic Capacity Number of Subjects A trait that has differential expression in >1% of the population Polymorphic Distribution

20 Examples of biotransformation reactions leading to a preferred marketed drug Drug Metabolism in drug design and development – Wiley Interscience – Fig 1.1

21 Examples of biotransformation reactions leading to a preferred marketed drug Drug Metabolism in drug design and development – Wiley Interscience – Fig 1.1 Desloratadine

22 Examples of biotransformation reactions leading to a preferred marketed drug Drug Metabolism in drug design and development – Wiley Interscience – Fig 1.1

23 Examples of biotransformation reactions leading to a preferred marketed drug Drug Metabolism in drug design and development – Wiley Interscience – Fig 1.1

24 (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

25 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig 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

26 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig The plateau plasma concentration of nortriptyline varies widely in 263 patients receiving a regime of 25 mg nortriptyline orally 3 times daily

27 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 13.2

28 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig The daily dose of warfarin required to produced a similar degree of anticoagulation in 200 adult patients varies widely

29 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig 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

30 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig Genetic plays a significant role in the maintenance dose requirement of warfarin used in the treatment of various cardiovascular diseases

31 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 13.3

32 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig The bimodal distribution of the 6-hr plasma isoniazid concentration in 483 subjects after 9.8 mg/kg isoniazid orally results from acetylation polymorphism

33 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

34 Enoxacin inhibits theophylline elimination Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 17.6

35 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 17.7

36 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

37 Inibidores de CYP3A Cetoconazole Fluconazole Itraconazole Cimetidina Claritromicina Eritromicina Suco de toronja

38 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)

39

40 Indutores de CYP3A Carbamazepina Rifampicina Rifabutina Ritonavir Hypericum perforatum

41 Faixa Normal Tempo de Protrombina (sec) Concentração de Warfarina (mg/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 Sep;81(3):

42 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 K l -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

43 Warfarin-phenylbutazone interaction Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig

44 Concentração de clozoxaona (mg/L) Horas Efeito da administração do dissulfiram no metabolismo da clorzoxazona Após dissulfiram (500mg v.o. 10h antes) Antes dissulfiram Clin. Pharmacol, 1993

45 Indução causada pelo pentobarbital Horas Concentração de Alprenolol (mg/L) Oral depois i.v. antesi.v. depois Oral antes Clin. Pharmacol. Ther., 1977

46 % de alteração AUCCLF Oral I.V. N.S. Efeito da cimetidina (400mg 6/6h 4d) na biodisponibilidade do labetolol J. Clin. Pharmacol, 1984

47 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

48 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig

49 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

50 Clarithomycin irreversibly inactivates CYP3A, the enzyme responsible for the metabolism of midazolam Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig

51 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

52 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

53 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

54 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 20.3

55 Alteração da hidroxilação de enantiômeros da mefenitoína Concentração Plasmática ( g/mL) Tempo (dias) R-mefenitoína S- mefenitoína R- mefenitoína S- mefenitoína T ½ = 2.13h T ½ = 76h A A B B

56 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

57 Two situation following constant-rate drug infusion are depicted Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 20.8

58 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig. 20.9

59 Classification of human P450s based on major substrate class Drug Metabolism in drug design and development – Wiley Interscience – Table 2.1

60 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

61 Common SULT substrate. Arrows indicate site of sulfonation for each Drug Metabolism in drug design and development – Wiley Interscience – Fig 3.6

62 Examples of CYP substrates and inhibitors used in clinical DDI studies Drug Metabolism in drug design and development – Wiley Interscience – Table 5.4

63 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

64 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Table 13-2 Some Genetic Polymorphisms in Pharmacodynamics

65 MEDICAMENTOS QUE SÃO METABOLIZADOS POR ISOFORMAS DO CITOCROMO P450 1A22B62C82C192C92D62E13A4,5,7 Clozapina Ciclobenzaprina Imipramina Naproxeno Teofilina Bupropiona Ciclofosfamida Efavirez Metadona Inibidores de Bomba de Próton: Omeprazole Lansoprazole Pantoprazole Rabeprazole Anti-epilépticos: Diazepam Fenitoína Fenobarbital Amitriptilina Clomipramina Ciclofosfamida Progesterona AINEs: Diclofenaco Ibuprofeno Piroxicam Hipoglicemiantes orais: Tolbutamida Glipizida Antagonistas de Angiotensina II: Irbesartan Losartan Celecoxib Fluvastatina Naproxeno Fenitoína Sulfametoxazole Tamoxifeno Tolbutamida Warfarina Betabloqueadores: S-metoprolol Timolol Antidepressivos: Amitriptilina Clomipramina Desipramina Imipramina Paroxetina Antipsicóticos: Haloperidol Risperidona Codeína Dextrometorfano Flecainida Ondansetrona Tamoxifeno Tramadol Venlafaxina Paracetamol Etanol 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 Bisórpma Gleevec, Haloperidol Metadona, Quinina Sildenafil Tamoxifeno Vincristina

66 INIBIDORES DE CITOCROMO P450 1A22B62C82C192C92D62E13A4,5,7 Cimetidina Fluoroquinolonas Fluvoxamin a Ticlopidina TiclopidinaGemfibrozila Montelukast Fluoxetina Fluvoxamina Cetoconazol Lansoprazol Omeprazol Ticlopidina Amiodarona Fluconazol Isoniazida Amiodarona Bupropriona Clorfeniramina Cimetidina Clomipramina Fluoxetina Haloperidol Metadona Paroxetina Quinidina Ritonavir DisulfiramInbidores de Protease: Indinavir Nelfinavir Ritonavir Amiodarone Cimetidina Claritromicina Diltiazem Eritromicina Fluvoxamina Itraconazol Cetoconazol Verapamil

67 INDUTORES DE CITOCROMO P450 1A22B62C82C192C92D62E13A4,5,7 Tabaco Fenobarbital Fenitoína Rifampicina Rifampicina Secobarbital N/AEtanol Isoniazida Carbamazepina Fenobarbital Fenitoína Rifabutina Rifampicina Hypericum perfuratum Troglitazona

68 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig Changes in the activity of CYP3A4 per milligram of protein in the duodenum of pediatric patients as a function of their age

69 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig Half-life od diazepam is shortest in the infant and logest in the newborn and the aged

70 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig Creatinine clearances of neonates on Day 1 and Day 6 after birth

71 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig Creatinine clearance, corrected (colored circles) and uncorrected (open circles) for body surface area, plotted versus conceptional age

72 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig 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).

73 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig The plateau plasma drug concentrations of two antiepileptic drugs, carvamazepine (A) and valproic acid (B). Are measured after chronic oral medication in children

74 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig

75 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig The minimum alveolar concentration (%) of desflurane required for general anesthesia varies with age

76 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Table 15.1 Comparison of the Pharmacokinetics of Selected Drugs in Healthy Subjects with that in Patients with Hepatic Cirrhosis

77 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Table 15.2 Child-Pugh Score for Assessing the Prognosis of Chronic Liver Disease (Mainly Cirrhosis)

78 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig Relationship between amprenavir AUC and the Child-Pugh score

79 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig Activities of the conjugating enzymes, glucuronyltransferase, sultransferase, acetyltransferaase, and glutathione transferase in normal (black) and abnormal (colored) human livers vary widely

80 NormalCirroseNormalCirrose o Meia-vida (h) do clordiazepóxido Clerance do clordiazepóxico (ml/min/kg) Clin. Pharmacol, 1979

81

82 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

83 Características da Barreira Hemato-Encefálica Targeted nanoparticles for drug delivery through the blood–brain barrier for Alzheimers disease C. Roney et al. / Journal of Controlled Release 108 (2005) 193–214

84 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

85 Mecanismos de Transporte na Barreira Hemato-Encefálica Targeted nanoparticles for drug delivery through the blood–brain barrier for Alzheimers disease C. Roney et al. / Journal of Controlled Release 108 (2005) 193–214

86 Concentrations (nCig) of [14C]-Amprenavir in CD-1 Mice Pretreated with GF and in FVB mdr la/lb Double Knockout Mice GF chemical knockoutmdr 1a/1b genetic double knockout TissueVehicleGF120918Ratio (+/+) (-/-) Ratio Blood46.3 ± ± ± ± Brain3.33 ± 0.6 a 43.8 ± ± ± CSF23.3 ± ± ± 6.8 NVND Testes15.2 ± ± ± ± Muscle33.0 ± ± ± ± Note: Data are the average from 3-4 animals ± the standard deviation. NV = Not visible. ND = not determined. Limit of Quantitation (LOQ): nCi/g. Sections had > 40% of pixels below quantification limit (BQL). Pharmaceutical Research, Vol. 16 No 8,1999

87 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

88 Initial brain uptake clearances (Cl up, mL·100g -1 ·min -1 )of opioids during in situ perfusion in mice CompoundOpioid receptor subtype Wild-type mice P-gp deficient mice P-gp effect Meperidineµ185 ± ± ± 0.27 Fentanylµ184 ± ± 9*1.24 ± 0.27 Morphineµ1.04 ± ± 0.08**1.24 ± 0.08 U-69593κ39.2 ± ± 8.8 a 1.34 ± 0.25 Bremazocineκ44.1 ± ± 3.8***1.50 ± 0.21 Deltophin IIδ0.166 ± ± **1.58 ± 0.36 Methadoneµ41.7 ± ± 17***2.61 ± 0.55 Naltrindoleδ12.5 ± ± 5.1 a 4.44 ± 0.93 SNC 121δ17.0 ± ± 15 a 8.60 ± 1.26 Loperamideµ9.86 ± ± 6***10.4 ±1.9 DPDPEδ ± ± ***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. Dagenais et al. / Biochemical Pharmacology 67 (2004) 269–276 – table 1

89 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

90 Indutores e Inibidores de Glicoproteína P IndutoresInibidores Rifampicina Ritonavir Hypericum perforatum Iohimbina 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

91 Horas após a Dose Concentração Felodipina (nmol/L) Suco de Toronja Água Estudo em dose única Horas após a Dose Pressão Arterial Sentado (min Hg) Efeito do suco de toronja na farmacocinética e farmacodinâmica da Felodipina

92 Hora (h) Concentração do Indinavir (μg/mL) Administrado após Hypericum perforatum Efeito do Hypericum perforatum na farmacocinética do Indinavir

93 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig 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. Johns wort 3 times daily (colored)

94 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

95 Applied – Biopharmaceutics & Pharmacokinetics – fig 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) Time (hours) Concetration (nmol/mL) Healthy Elderly

96 Felodipina (5mg) via oral Idade Palpitação3/111/12 Rubor9/111/12 Clearance248 mL/h619 mL/h

97

98 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

99 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig

100 Concentração plasmática de salicilamida após várias administração por via oral em distintas doses Concentração Plasmática Salicilamida (mg/L) Concentração Plasmática Salicilamida (mg/L) Minutos

101 Typical Pharmacokinetics Parameters of Digoxin in the Absence and Presence of Quinidine Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Table 17.7

102 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

103 Applied Clinical Pharmacokinetics – Larry Bauer – Eq; pag 19 ????????????????????????????????

104

105 Applied Clinical Pharmacokinetics – Larry Bauer – Fig. 3-4 Relationship between creatinine creatinine clearance and aminoglycoside elimination rate constant (k e ) to estimate initial aminoglycoside elimination when no drug concentrations are available. The y-axis intercept (0.014h -1 ) is nonrenal elimination for aminoglycosides

106 Applied Clinical Pharmacokinetics – Larry Bauer – Fig. 3-3 Relationship between creatinine clearance and digoxin clearance to estimate initial digoxin clearance when no drug concentrations are available

107 Idade (anos) CL/F (ml h -1 kg -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)

108 CL/F (ml h -1 kg -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 = 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)

109 CL/F (ml h -1 kg -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) Influence of aging on serum phenytoin concentrations: a pharmacokinetic analysis based on therapeutic drug monitoring data – Epilepsy Research 59 (2004)

110 CL/F (ml h -1 kg -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 = 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)

111 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)

112 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig Schematic representation of a hemodialysis system in which drug is passively transferred across a semipermeable mambrane (---) from blood to dialysate

113 Applied Clinical Pharmacokinetics – Larry Bauer – Fig Concentration-time graph for tombramycin in a hemodialysis patients using estimated population pharmacokinetics parameters

114 Fenobarbital em paciente renal terminal de 70kg Vu= 77L Clu = -.4 L/h k= 0.005/hr t1/2 = 137 h

115 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig Plasma dialysis clearance and unbound dialysis clearance with an adjustment for molecular size for 27 different drugs show considerable variability

116 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig 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

117 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig

118 Clinical Pharmacokinetics and Pharmacodynamics – Concepts and Applications – Fourth Edition – Fig Relationship between systemic bioavailability (mean ± SD of five patients) and dwell time when teicoplanin is administered intraperioneally

119 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.

120 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

121 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 = 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.


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