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Dúvidas denucci@ gilbertodenucci.com Arquivo Administração de drogas por via oral Site: www.gilbertodenucci.com

Dúvidas denucci@ gilbertodenucci.com Arquivo Administração de drogas por via oral Site: www.gilbertodenucci.com. Administração de um comprimido de 500 mg de Amoxicilina a um voluntário sadio – curva de concentração em função do tempo. 7. 6. 5. 4. Concentração Plasmática. (mg/L). 3.

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Dúvidas denucci@ gilbertodenucci.com Arquivo Administração de drogas por via oral Site: www.gilbertodenucci.com

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  1. Dúvidas denucci@gilbertodenucci.com Arquivo Administração de drogas por via oral Site: www.gilbertodenucci.com

  2. Administração de um comprimido de 500 mg de Amoxicilina a um voluntário sadio – curva de concentração em função do tempo 7 6 5 4 Concentração Plasmática (mg/L) 3 2 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Tempo (h)

  3. Administração de uma cápsula de 150 mg de Venlafaxina a um voluntário sadio – curva de concentração em função do tempo

  4. Administração de um comprimido de 5 mg de Amlodipina a um voluntário sadio – curva de concentração em função do tempo 7.5 5.0 (µg/L) Concentração Plasmática 2.5 0.0 0 2 4 6 8 10 12 14 24 48 72 96 120 144 Tempo (h)

  5. 7.5 5.0 (µg/L) Concentração Plasmática 2.5 0.0 0 2 4 6 8 10 12 14 24 48 72 96 120 144 Tempo (h) Administração de um comprimido de 5 mg de Amlodipina a um voluntário sadio – área sob a curva ASC

  6. Biodisponibilidade absoluta (F) ASC VO F = ASC EV Medicamento administrado na mesma dose

  7. Como calcular a biodisponibilidade (F)? ASC VO vs dose e.v. F = ASC EV vs dose v.o.

  8. Biodisponibilidade relativa ASC VO teste Frel = ASC VO referência

  9. Biodisponibilidade A fração da droga não modificada que atinge a circulação sistêmica independente da via de administração Biodisponibilidade absoluta – via oral comparada à via endovenosa Biodisponibilidade relativa – comparação de duas outras vias

  10. Administração Oral Luz Intestinal Parede Intestinal Fígado Veia Porta Local de Medida Metabolismo Metabolismo Fezes

  11. Infarto do Miocárdio

  12. Infarto do Miocárdio

  13. Infarto do Miocárdio

  14. Biodisponibilidade (F) Total F = FL . FP. FF FL = luz intestinal FP = parede intestinal FF = fígado

  15. Efeito do tempo de esvaziamento gástrico na absorção do acetaminofeno 15 10 5 0 Metoclopramida (10 mg i.v.) sózinho Propantelina (30 mg i.v.) Concentração Plasmática de Acetaminofeno (mg/L) 0 1 2 3 4 5 Horas

  16. Influência da alimentação no Cmax do Paracetamol 40 ) 30 -1 g.ml m * ( 20 ** max C 10 0 Jejum Continental Inglês * P<0.05 comparado com jejum ** P<0.01 comparado com jejum

  17. Influência da alimentação no Tmax do Paracetamol 2.0 ** 1.5 # * (h) max 1.0 t 0.5 0.0 Jejum Continental Inglês * P<0.05 comparado com jejum ** P<0.01 comparado com jejum # P< 0.05 comparado com café da manhã inglês

  18. Influência da alimentação no AUC0-inf do Paracetamol 75 .h) -1 g.ml 50 m ( 0-inf 25 AUC 0 Jejum Continental Inglês

  19. Influência da alimentação no Cmax da Nifedipina (liberação imediata) 100 ** ) 75 -1 g.ml m ( 50 max C 25 0 Jejum Continental Inglês ** P<0.01 comparado com jejum

  20. Influência da alimentação no Tmax da Nifedipina (liberação imediata) 7.5 5.0 (h) max t 2.5 0.0 Jejum Continental Inglês

  21. Influência da alimentação no AUC0-inf da Nifedipina (liberação imediata) 750 .h) -1 g.ml 500 m ( 0-inf 250 AUC 0 Jejum Continental Inglês

  22. Efeito do tipo de alimentação na absorção do posaconazol (suspensão 200mg) 600 550 500 450 400 350 300 250 200 150 100 50 0 Susp alim gorduroso Cp alim gorduroso Susp alim pouco gorduroso Concentração plasmática (mg/ml-1) Susp jejum 0 12 24 36 48 60 72 Tempo (h)

  23. Tetracyclines • The bioavailability of tetracycline is reduced by 46 to 57% when taken with food, by 50 to 65% when taken with dairy products and by up to 81% when taken with iron supplements because of chelation. This interaction may result in treatment failure in cases involving pathogens with a moderate resistance to tetracycline. • Even the use of a small volume of milk in tea or coffee is sufficient to cause a 49% reduction in tetracycline bioavailability.

  24. ACE Inhibitors Food intake decreases the bioavailability of captopril by 42 to 56%. Food intake also decreases the bioavailability of perindopril by 35% which is associated with a clinically significant decrease in ACE inhibition. The bioavailability of cilazapril, enalapril and lisinopril is unaffected by food intake.

  25. Mean plasma concentration-time profiles of irbesartan after administration of a 300-mg tablet to 16 healthy volunteers under fasted and fed conditions

  26. The bioavailability of lovastatin increases by 50% when taken with a regular meal; this is reflected in an increased drug effect. In contrast, the ingestion of fibres or fruit as part of a lipid-lowering diet may strikingly reduce the absorption of lovastatin and increase the risk of treatment failure.[89]

  27. The bioavailability of pravastatin is reduced by when taken with food; however, since its lipid-lowering efficacy is unchanged the interaction is not clinically important. For atorvastatin and fluvastatin, bioavailability and lipid-lowering efficacy are unaffected by food intake.

  28. Excessive ingestion of grapefruit juice increases the bioavailability of lovastatin, atorvastatin and simvastatin by 1400, 200 and 1500%, respectively

  29. The bioavailability of tetracycline is reduced by 46 to 57% when taken with food, by 50 to 65% when taken with dairy products and by up to 81% when taken with iron supplements because of chelation. This interaction may result in treatment failure in cases involving pathogens with a moderate resistance to tetracycline. Even the use of a small volume of milk in tea or coffee is sufficient to cause a 49% reduction in tetracycline bioavailability.

  30. Physicochemical and Physiological Mechanisms for the Effects of Food on Drug Absorption: The Role of Lipids and pH Journal of Pharmaceutical Sciences / American Pharmaceutical Association Vol. 86, No. 3, March 1997

  31. Permeabilidade Peso molecular Lipofilicidade Carga Espessuradamembrana

  32. Permeabilidade Peso molecular Lipofilicidade • Carga Espessuradamembrana

  33. Henderson-Hasselbach para ácidos ( ) pH = pKa + log10 [Ionizada] [Não-ionizada]

  34. Henderson-Hasselbach para bases ( ) pH = pKa + log10 [Não-ionizada] [Ionizada]

  35. Ácidos Bases pka Forte Fraco 0 Cafeína Dapsona Oxazepam Nitrazepam Diazepam Quinidina Clordiazepóxido Propoxifeno Reserpina Cimetidina Lidocaína Quinina Meperidina Procainamida Efedrina Anfetamina Tolazolina Mecamilamina Guanetidina 1 Acido cromoglícico Penicilinas Ácido Salicílico AAS Varfarina Tolbutamida Sulfadimetoxina Tiopental Fenitoína Teofilina Glutetimida Nitrazepan Oxazepan Cafeína 2 3 4 5 6 } Acetazolamida Fenobarbital 7 8 9 10 11 12 13 Forte Fraco 14

  36. Absorção do ácido salicílico (pKa =3) 100 80 60 40 20 0 Estômago, pH3 Percentagem da droga que resta para ser absorvida Intestino, pH6 0 20 40 60 80 Minutos

  37. pH in various biological media together with surface area at which the biological media is represented (Wilson, 1967; Newton and Kluza, 1978; Madara, 1991; Dressman et al ., 1993; Gray and Dressman, 1996; Kutchai, 1996; Charman et al., 1997, Dressman et al., 1998; Avdeef, 2001) Book: Molecular Biopharmaceutics – Part 2 – Table 2.1.2 – pag. 13

  38. Excreção Urinária de Metanfetamina Diurese Ácida (pH 4.9-5.3) 6 4 2 0 Quantidade de Metanfetamina Excretada Sem controle pH Diurese Alcalina (pH 7.8-8.2) 0 4 8 12 16 Horas Nature, 1965

  39. Clearance Renal do Ácido Salicílico 250 200 150 100 50 0 Clerance Renal (mL/min) 5.5 6 6.5 7 7.5 8 8.5 pH Urinário J. Pharmacol. Exp. Ther. 1946

  40. Influência do pH no clearance renal da dietilcarbamziazina pH Urinário Clerance Renal (L/hr) Não controlado (6.3) 8.6 Diurese ácida <5.5 38.0 Diurese alcalina >7.5 1.0

  41. Clearance do fenobarbital 12 Diurese alcalina 8 Diurese normal Clearance Renal do Fenobarbital (mL/min) 4 0 0 4 8 12 16 Fluxo Urinário (mL/min) Lancet, 1967

  42. Administração de itraconazol (100 mg) em voluntários sadios Treatmento I (controle) água Treatmento II Coca-Cola 0.25 0.2 0.15 Concentração Plasmática (mg/L) 0.1 0.05 0 0 4 8 12 16 20 24 Tempo (h)

  43. Dermatological Agents • The bioavailability of the anti-acne agent isotretinoin is increased by 72 to 86% when administered with or shortly after a meal.[76] Because isotretinoin dosage is titrated according to drug effect and the appearance of adverse effects, the drug should be taken with a consistent relationship to meals. • Food intake increases the bioavailability of the antipsoriatic agent acitretin by 91% and reduces the interpatient variability in bioavailability.[5] Accordingly, coadministration of acitretin with food may be preferred.

  44. Oral Bioavailability Parameters for Halofantrine HCl After Administration to Either Fasted or Fed Healthy Human Subjects and Fasted or Fed Beagle Dogs Bioavailability Parameter3 Plasma AUC (mg h/L) Cmax (ng/mL) Human Subjects Fasted Fed 3.9 ± 2.6 11.3 ± 3.5 184 ± 115 1218 ± 464 Beagles Subjects Fasted Fed 4.2 ± 2.7 51.5 ± 9.4 275 ± 156 5540 ± 2107 Physicochemical and Physiological Mechanisms for the Effects of Food on Drug Absorption: The Role of Lipids and pH Journal of Pharmaceutical Sciences / American Pharmaceutical Association Vol. 86, No. 3, March 1997

  45. Examples of incread Postprandial Oral Bioavailability and Likely Basis for the Increased Absorption Compound Griseofulvin Danazol Α-Tocopheryl nicotinate Halofantrine Atovaquone Retinoic acid derivates Increase in Bioavailability 3-5-fold (humans) 4-fold (humans) 5-fold (dogs) 28-fold (humans) 10-fold (dogs) 3-fold (humans) 3-5-fold (humans) 2-5-fold (humans) Basis for Food Effect ↑ solubilization → portal blood transport ↑ solubilization → portal blood transport ↑ solubilization → portal blood and lymph transport ↑ solubilization → portal blood transport possible lymph transport ↑ solubilization → portal blood transport Likely ↑ solubilization → portal blood transport possible lymph transport Physicochemical and Physiological Mechanisms for the Effects of Food on Drug Absorption: The Role of Lipids and pH Journal of Pharmaceutical Sciences / American Pharmaceutical Association Vol. 86, No. 3, March 1997

  46. Efeito da alimentação na absorção de nifedipina administrada por duas formulações de liberação prolongada ADALAT® OROS fasted 100 75 50 25 0 ADALAT® OROS fed CORAL® fasted CORAL® fed Concentração plasmática (μg/L) 0 5 10 15 20 25 30 35 40 45 50 Tempo (h)

  47. Since dissolution rate is a function of surface area, a nano-formulation will have better bioavailability than a micronized formulation of the same drug where bioavailability is dissolution rate limited

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