Description
This is a presentation about banned drugs, concept of therapeutic window, different mechanisms and alterations in absorption.
PHARMACOKINETIC DRUG INTERACTIONS
DRUGS REMOVED FROM THE MARKET DURING THE 1990s
DRUG Astemizole CATEGORY antihistamine REASON serious metabolic drug intxns hepatotoxicity cardiovascular tox aplastic anemia increased mortality proarrhythmic serious drug intxns severe ADR serious drug intxn hepatotoxicity
Bromfenac analgesic Dexfenfluramine anorectic Felbamate anticonvulsant Flosequinan vasodilator Grepafloxacin antibiotic Mibefradil Ca channel blocker Temafloxacin antibiotic Terfenadine antihistamine Travafloxacin antibiotic Source: J Clin Pharmacol 40:1093, 2000
I. GENERAL CONSIDERATIONS
A. CONCEPT OF A THERAPEUTIC WINDOW
Desired Probability of Response
Toxicity
log Concentration
B. EPIDEMIOLOGICAL CONSIDERATIONS
HOSPITALIZED PATIENTS EXPERIENCING AN ADVERSE REACTION Drug Class Antihypertensives Anticoagulants Antimicrobials Antiarrhythmics Antiinflammatory Diuretics Analgesics % Pts with Reaction 12 11 6 4 3 3 2
Data from: May FE et,al. Drug interactions and multiple drug administration. Clin Pharmacol Ther 22:323, 1977.
B. EPIDEMIOLOGICAL CONSIDERATIONS
Effect of the Number of Drugs a Patient Receives on the Frequency of Adverse Drug Reactions Number 0-5 6-10 11-15 16-20 Antihypertensives 9 9 18 23 Anticoagulants 7 8 15 18
Data from: May FE et,al. Drug interactions and multiple drug administration. Clin Pharmacol Ther 22:323, 1977.
B. EPIDEMIOLOGICAL CONSIDERATIONS
Prospective study of 237 patients treated with warfarin analyzed for determination of whether or not a drug interaction occurred with concurrent chloral hydrate All patients who received chloral hydrate during warfarin therapy Those patients who received chloral hydrate for at least 3 consecutive days Impossible to evaluate (unstable/change therapy) Potentiation of anticoagulant action No observable interaction 237
69 28 22 19
Data from: Koch-Weser J. Hemorrhagic reactions and drug interactions in 500 warfarin treated patients. Clin Pharmacol Ther 14:139-146, 1973.
C. TYPE OF INTERACTION
Unidirectional
A
Bidirectional
B B
A
D. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTION
Complexation/Chelation Example: antacids + tetracycline Impact: tetracycline complexes with divalent cations forming an insoluble complex
D. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTION
Complexation/Chelation
Altered GI Transit Example: anticholinergics + acetaminophen
Impact: delay in absorption of acetaminophen
D. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTION
Complexation/Chelation
Altered GI Transit
Altered Gastric pH Example: H-2 blockers + ketoconazole Impact: dissolution of ketoconazole is decreased, resulting in reduced absorption
D. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTION ALTERATIONS IN HEPATIC METABOLISM
Induction of Metabolism Example: phenobarbital + warfarin Impact: phenobarbital increases the metabolism of warfarin, resulting in reduced anticoagulation
D. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTION ALTERATIONS IN HEPATIC METABOLISM
Induction of Metabolism Inhibition of Metabolism Example: cimetidine + theophylline Impact: cimetidine reduces the clearance of theophylline causing an increase in adverse effects
D. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTION ALTERATIONS IN HEPATIC METABOLISM ALTERATIONS IN RENAL CLEARANCE
Increase in Renal Blood Flow Example: hydralazine + digoxin
Impact: hydralazine increases the renal clearance of digoxin
D. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTION ALTERATIONS IN HEPATIC METABOLISM ALTERATIONS IN RENAL CLEARANCE
Increase in Renal Blood Flow Inhibition of Active Tubular Secretion Example: probenecid + penicillin
Impact: probenecid prolongs the half-life of penicillin, allowing single dose therapy
D. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTION ALTERATIONS IN HEPATIC METABOLISM ALTERATIONS IN RENAL CLEARANCE
Increase in Renal Blood Flow Inhibition of Active Tubular Secretion Alterations in Tubular Reabsorption Example: antacids + aspirin
Impact: antacids reduce the tubular reabsorption of salicylate via an increase in urine pH
D. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTION ALTERATIONS IN HEPATIC METABOLISM ALTERATIONS IN RENAL CLEARANCE ALTERATIONS IN PLASMA PROTEIN BINDING
Example: phenytoin + valproic acid Impact: protein binding of valproic acid is reduced and total Css decreased
II. ALTERATIONS IN ABSORPTION
A. Mediated by binding or chelation of drug in the gastrointestinal tract
HO COOH CH3 NH-NH2
HO
carbidopa
HO
COOH NH2
L-dopa
HO
Plasma carbidopa (nmol/ml)
0.2 0.15 0.1 0.05 0 0 200 400
5 4 3 2 1 0 0 200
Plasma Levodopa (nmol/ml)
Time (min)
400
Time (min)
Effect of ferrous sulfate (325 mg) on plasma levodopa and carbidopa concentrations after ingestion of Sinemet (100/25) in patients with Parkinson's disease. Concentrations shown are mean values without (tirangles) and with (circles) ferrous sulfate administration simultaneously.
Adapted from Campbell NRC et al: Br J clin Pharmacol 30:599-605, 1990
Effect of Antacids on Iron Absorption from a Multivitamin. Antacid was ingested immediately after multivitamin ingestion. Data from: O'Neil-Cutting MA, Crosby WH. The effect of antacids on the absorption of simultaneously ingested iron. JAMA 255:1468- 1470, 1986.
80
2-hr plasma iron increase (mcg/dl)
60 40 20 0
Control Antacid
Mylanta II
Na Carbonate
Ca Carbonate
COMPOUNDS DEMONSTRATED TO BIND WITH IRON
ACETAMINOPHEN AMPICILLIN CAPTOPRIL CARBIDOPA CIPROFLOXACIN ETHAMBUTOL FOLIC ACID INDOMETHACIN LEVODOPA METHYLDOPA MINOXIDIL NALIDIXI ACID NORFLOXACIN PENICILLAMINE RIFAMPIN TETRACYCLINE THYROXINE SALICYLIC ACID
B. Mediated by alterations in gastric emptying or gastrointestinal transit
? 11 10 9 8 7 6 GRT (hr) 5 4 3 2 1 ?? ? ? ? ?? ? ? Fasting ? ? ? ? ? ? ?
Effect of food on gastric residence time (GRT) of the Heidelberg capsule administered to healthy male (circles) and female (squares).
Reproduced from: Mojaverian P et al. Effect of food on the absorption of enteric coated aspirin: Correlation with gastric residence time. Clin Pharmacol Ther 41:11-17, 1987.
Fed
Male
Total Salicylate (mcg/ml)
10
Fasted Fed
1 0 10 20 30
100
Total Salicylate (mcg/ml)
Female Fasted Fed 10
Time (hr)
1 0 10 20 Time (hr) 30 40
Reproduced from: Rowland M,Tozer TN. Clinical Pharmacokinetics – Concepts and Applications, 3rd edition, 1995, p.271
Effect of sumatriptan on acetaminophen absorption in patients with migraines
Parameter
Cmax (mg/L) tmax (hr) t1/2 (hr) AUC0-1.5 AUC0-3 AUC0-8
APAP alone with Sumatriptan
36.3 (10.9) 1.4 (0.4) 2.3 (0.7) 26.9 (9.5) 62.3 (14) 109 (37) 18.3 (6.7) 2.7 (1.0) 3.0 (1.4) 11.8 (3.7) 33.1 (12.9) 78.8 (31.3)
p value
0.001 0.001 NS 0.001 0.001 NS
Data from: Rani PU, et al. Sumatriptan delays paracetamol absorption in migraine patients. Clin Pharmacokinet 11:300-304, 1996.
III. ALTERATIONS IN DRUG METABOLISM
A. Induction
QH f ubCLu int CLH ? QH ? f ubCLu int F ? Dose AUCO ? f ubCLu int
Effect of phenobarbital (60 mg qd) on dicumarol plasma concentrations and prothrombin time. From: Cucinell SA, et al. Lowering effect of phenobarbital on plasma levels
of dicumarol and diphenylhydantion. Clinical Pharmacology & Therapeutics 6:420-429, 1965.
Reproduced from: Twum-Barima Y, Carruthers SG. Quinidine-rifampin interaction. NEJM 304:1466, 1981.
From: Rowland M, Tozer TN. Ibid. p. 282.
B. Inhibition
20
Clearance (ml/min)
Control Cimetidine
15 10 5 0 D DZD CZD
OXM
Effect of cimetidine on the clearance on diazepam (D), desmethyldiazepam (DZD), chlordiazepoxide (CZD) and oxazepam (OXM). CZD values are x10, while OXM values are 1/10. Data from: Somogyi A, Gugler R: Drug interactions with cimetidine. Clin
Pharmacokinet 7:23, 1982.
Norfloxacin O floxacin Pe floxacin Ciprofloxacin Enoxacin
0
20
40
60
80
% Decrease in Theophylline CL
Summary of studies assessing effect of quinolones on theophylline clearance. Data from: Edwards DJ, Bowles SK, Svensson CK, Rybak MJ. Clin Pharmacokinet 15:194, 1988.
FACTORS WHICH ALTER HEPATIC BLOOD FLOW
Increased Flow •Glucagon •Isoproterenol •Phentolamine •Phenobarbital •PGE •Supine posture •High-protein meal •Viral hepatitis Decreased Flow •Propranolol •Norepinephrine •Anesthetics •Labetalol •Upright posture •Hypovolemia •CHF •cirrhosis
Effect of changing posture on liver blood flow and lidocaine clearance
Parameter Supine Sitting/tilted
QH (mL/min) CL (mL/min)
1100 (167) 602 (101)
765 (106) 475 (109)
Data presented as mean (SD)
From: Feely J, et al. Effect of hypotension on liver blood flow and lidocaine disposition. N Engl J Med 307:866-869, 1982.
V. ALTERATIONS IN RENAL CLEARANCE A. Renal Blood Flow
Control 250 200 150 100 50 0 Nitroprusside Hydralazine
Percent of control Value
CI
PAH RBF
Dig CLr
Effect of vasodilators on hemodynamics, renal function and digoxin renal excretion. CI - cardiac index,; PAH - p-aminohippuric acid clearance; RBF -renal blood flow; and Dig CLr - digoxin renal clearance. Data from Cogan JJ, et al. Circulation 64:973, 1981.
B. Active Tubular Secretion
B. Urine pH
Salicylic acid renal clearance (ml/min)
20 16 12 8 4 0 4 5 6 Urine pH 7 8
Renal clearance of salicylate in 11 yo child with rheumatic fever treated with an antacid. Data from Levy G, Lampman T, Kamath BL, Garrettson LK. Decreased serum salicylate concentrations in children with rheumatic fever treated with antacid. N Engl J Med 293:323-325, 1975.
VI. ALTERATIONS IN PROTEIN BINDING
From: Rowland M, Tozer TN. Ibid, p. 274.
Reproduced from: Rowland M, Tozer TN. Ibid, p. 280
From: Rowland M, Tozer TN. Ibid, p. 275.
doc_948366559.ppt
This is a presentation about banned drugs, concept of therapeutic window, different mechanisms and alterations in absorption.
PHARMACOKINETIC DRUG INTERACTIONS
DRUGS REMOVED FROM THE MARKET DURING THE 1990s
DRUG Astemizole CATEGORY antihistamine REASON serious metabolic drug intxns hepatotoxicity cardiovascular tox aplastic anemia increased mortality proarrhythmic serious drug intxns severe ADR serious drug intxn hepatotoxicity
Bromfenac analgesic Dexfenfluramine anorectic Felbamate anticonvulsant Flosequinan vasodilator Grepafloxacin antibiotic Mibefradil Ca channel blocker Temafloxacin antibiotic Terfenadine antihistamine Travafloxacin antibiotic Source: J Clin Pharmacol 40:1093, 2000
I. GENERAL CONSIDERATIONS
A. CONCEPT OF A THERAPEUTIC WINDOW
Desired Probability of Response
Toxicity
log Concentration
B. EPIDEMIOLOGICAL CONSIDERATIONS
HOSPITALIZED PATIENTS EXPERIENCING AN ADVERSE REACTION Drug Class Antihypertensives Anticoagulants Antimicrobials Antiarrhythmics Antiinflammatory Diuretics Analgesics % Pts with Reaction 12 11 6 4 3 3 2
Data from: May FE et,al. Drug interactions and multiple drug administration. Clin Pharmacol Ther 22:323, 1977.
B. EPIDEMIOLOGICAL CONSIDERATIONS
Effect of the Number of Drugs a Patient Receives on the Frequency of Adverse Drug Reactions Number 0-5 6-10 11-15 16-20 Antihypertensives 9 9 18 23 Anticoagulants 7 8 15 18
Data from: May FE et,al. Drug interactions and multiple drug administration. Clin Pharmacol Ther 22:323, 1977.
B. EPIDEMIOLOGICAL CONSIDERATIONS
Prospective study of 237 patients treated with warfarin analyzed for determination of whether or not a drug interaction occurred with concurrent chloral hydrate All patients who received chloral hydrate during warfarin therapy Those patients who received chloral hydrate for at least 3 consecutive days Impossible to evaluate (unstable/change therapy) Potentiation of anticoagulant action No observable interaction 237
69 28 22 19
Data from: Koch-Weser J. Hemorrhagic reactions and drug interactions in 500 warfarin treated patients. Clin Pharmacol Ther 14:139-146, 1973.
C. TYPE OF INTERACTION
Unidirectional
A
Bidirectional
B B
A
D. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTION
Complexation/Chelation Example: antacids + tetracycline Impact: tetracycline complexes with divalent cations forming an insoluble complex
D. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTION
Complexation/Chelation
Altered GI Transit Example: anticholinergics + acetaminophen
Impact: delay in absorption of acetaminophen
D. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTION
Complexation/Chelation
Altered GI Transit
Altered Gastric pH Example: H-2 blockers + ketoconazole Impact: dissolution of ketoconazole is decreased, resulting in reduced absorption
D. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTION ALTERATIONS IN HEPATIC METABOLISM
Induction of Metabolism Example: phenobarbital + warfarin Impact: phenobarbital increases the metabolism of warfarin, resulting in reduced anticoagulation
D. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTION ALTERATIONS IN HEPATIC METABOLISM
Induction of Metabolism Inhibition of Metabolism Example: cimetidine + theophylline Impact: cimetidine reduces the clearance of theophylline causing an increase in adverse effects
D. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTION ALTERATIONS IN HEPATIC METABOLISM ALTERATIONS IN RENAL CLEARANCE
Increase in Renal Blood Flow Example: hydralazine + digoxin
Impact: hydralazine increases the renal clearance of digoxin
D. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTION ALTERATIONS IN HEPATIC METABOLISM ALTERATIONS IN RENAL CLEARANCE
Increase in Renal Blood Flow Inhibition of Active Tubular Secretion Example: probenecid + penicillin
Impact: probenecid prolongs the half-life of penicillin, allowing single dose therapy
D. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTION ALTERATIONS IN HEPATIC METABOLISM ALTERATIONS IN RENAL CLEARANCE
Increase in Renal Blood Flow Inhibition of Active Tubular Secretion Alterations in Tubular Reabsorption Example: antacids + aspirin
Impact: antacids reduce the tubular reabsorption of salicylate via an increase in urine pH
D. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTION ALTERATIONS IN HEPATIC METABOLISM ALTERATIONS IN RENAL CLEARANCE ALTERATIONS IN PLASMA PROTEIN BINDING
Example: phenytoin + valproic acid Impact: protein binding of valproic acid is reduced and total Css decreased
II. ALTERATIONS IN ABSORPTION
A. Mediated by binding or chelation of drug in the gastrointestinal tract
HO COOH CH3 NH-NH2
HO
carbidopa
HO
COOH NH2
L-dopa
HO
Plasma carbidopa (nmol/ml)
0.2 0.15 0.1 0.05 0 0 200 400
5 4 3 2 1 0 0 200
Plasma Levodopa (nmol/ml)
Time (min)
400
Time (min)
Effect of ferrous sulfate (325 mg) on plasma levodopa and carbidopa concentrations after ingestion of Sinemet (100/25) in patients with Parkinson's disease. Concentrations shown are mean values without (tirangles) and with (circles) ferrous sulfate administration simultaneously.
Adapted from Campbell NRC et al: Br J clin Pharmacol 30:599-605, 1990
Effect of Antacids on Iron Absorption from a Multivitamin. Antacid was ingested immediately after multivitamin ingestion. Data from: O'Neil-Cutting MA, Crosby WH. The effect of antacids on the absorption of simultaneously ingested iron. JAMA 255:1468- 1470, 1986.
80
2-hr plasma iron increase (mcg/dl)
60 40 20 0
Control Antacid
Mylanta II
Na Carbonate
Ca Carbonate
COMPOUNDS DEMONSTRATED TO BIND WITH IRON
ACETAMINOPHEN AMPICILLIN CAPTOPRIL CARBIDOPA CIPROFLOXACIN ETHAMBUTOL FOLIC ACID INDOMETHACIN LEVODOPA METHYLDOPA MINOXIDIL NALIDIXI ACID NORFLOXACIN PENICILLAMINE RIFAMPIN TETRACYCLINE THYROXINE SALICYLIC ACID
B. Mediated by alterations in gastric emptying or gastrointestinal transit
? 11 10 9 8 7 6 GRT (hr) 5 4 3 2 1 ?? ? ? ? ?? ? ? Fasting ? ? ? ? ? ? ?
Effect of food on gastric residence time (GRT) of the Heidelberg capsule administered to healthy male (circles) and female (squares).
Reproduced from: Mojaverian P et al. Effect of food on the absorption of enteric coated aspirin: Correlation with gastric residence time. Clin Pharmacol Ther 41:11-17, 1987.
Fed
Male
Total Salicylate (mcg/ml)
10
Fasted Fed
1 0 10 20 30
100
Total Salicylate (mcg/ml)
Female Fasted Fed 10
Time (hr)
1 0 10 20 Time (hr) 30 40
Reproduced from: Rowland M,Tozer TN. Clinical Pharmacokinetics – Concepts and Applications, 3rd edition, 1995, p.271
Effect of sumatriptan on acetaminophen absorption in patients with migraines
Parameter
Cmax (mg/L) tmax (hr) t1/2 (hr) AUC0-1.5 AUC0-3 AUC0-8
APAP alone with Sumatriptan
36.3 (10.9) 1.4 (0.4) 2.3 (0.7) 26.9 (9.5) 62.3 (14) 109 (37) 18.3 (6.7) 2.7 (1.0) 3.0 (1.4) 11.8 (3.7) 33.1 (12.9) 78.8 (31.3)
p value
0.001 0.001 NS 0.001 0.001 NS
Data from: Rani PU, et al. Sumatriptan delays paracetamol absorption in migraine patients. Clin Pharmacokinet 11:300-304, 1996.
III. ALTERATIONS IN DRUG METABOLISM
A. Induction
QH f ubCLu int CLH ? QH ? f ubCLu int F ? Dose AUCO ? f ubCLu int
Effect of phenobarbital (60 mg qd) on dicumarol plasma concentrations and prothrombin time. From: Cucinell SA, et al. Lowering effect of phenobarbital on plasma levels
of dicumarol and diphenylhydantion. Clinical Pharmacology & Therapeutics 6:420-429, 1965.
Reproduced from: Twum-Barima Y, Carruthers SG. Quinidine-rifampin interaction. NEJM 304:1466, 1981.
From: Rowland M, Tozer TN. Ibid. p. 282.
B. Inhibition
20
Clearance (ml/min)
Control Cimetidine
15 10 5 0 D DZD CZD
OXM
Effect of cimetidine on the clearance on diazepam (D), desmethyldiazepam (DZD), chlordiazepoxide (CZD) and oxazepam (OXM). CZD values are x10, while OXM values are 1/10. Data from: Somogyi A, Gugler R: Drug interactions with cimetidine. Clin
Pharmacokinet 7:23, 1982.
Norfloxacin O floxacin Pe floxacin Ciprofloxacin Enoxacin
0
20
40
60
80
% Decrease in Theophylline CL
Summary of studies assessing effect of quinolones on theophylline clearance. Data from: Edwards DJ, Bowles SK, Svensson CK, Rybak MJ. Clin Pharmacokinet 15:194, 1988.
FACTORS WHICH ALTER HEPATIC BLOOD FLOW
Increased Flow •Glucagon •Isoproterenol •Phentolamine •Phenobarbital •PGE •Supine posture •High-protein meal •Viral hepatitis Decreased Flow •Propranolol •Norepinephrine •Anesthetics •Labetalol •Upright posture •Hypovolemia •CHF •cirrhosis
Effect of changing posture on liver blood flow and lidocaine clearance
Parameter Supine Sitting/tilted
QH (mL/min) CL (mL/min)
1100 (167) 602 (101)
765 (106) 475 (109)
Data presented as mean (SD)
From: Feely J, et al. Effect of hypotension on liver blood flow and lidocaine disposition. N Engl J Med 307:866-869, 1982.
V. ALTERATIONS IN RENAL CLEARANCE A. Renal Blood Flow
Control 250 200 150 100 50 0 Nitroprusside Hydralazine
Percent of control Value
CI
PAH RBF
Dig CLr
Effect of vasodilators on hemodynamics, renal function and digoxin renal excretion. CI - cardiac index,; PAH - p-aminohippuric acid clearance; RBF -renal blood flow; and Dig CLr - digoxin renal clearance. Data from Cogan JJ, et al. Circulation 64:973, 1981.
B. Active Tubular Secretion
B. Urine pH
Salicylic acid renal clearance (ml/min)
20 16 12 8 4 0 4 5 6 Urine pH 7 8
Renal clearance of salicylate in 11 yo child with rheumatic fever treated with an antacid. Data from Levy G, Lampman T, Kamath BL, Garrettson LK. Decreased serum salicylate concentrations in children with rheumatic fever treated with antacid. N Engl J Med 293:323-325, 1975.
VI. ALTERATIONS IN PROTEIN BINDING
From: Rowland M, Tozer TN. Ibid, p. 274.
Reproduced from: Rowland M, Tozer TN. Ibid, p. 280
From: Rowland M, Tozer TN. Ibid, p. 275.
doc_948366559.ppt