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PHARMACOKINETICPHARMACOKINETIC
DRUG INTERACTIONSDRUG INTERACTIONS
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DRUGS REMOVED FROM THE MARKETDRUGS REMOVED FROM THE MARKET
DURING THE 1990sDURING THE 1990s
DRUG CATEGORY REASON
Astemizole antihistamine serious metabolic
drug intxns
Bromfenac analgesic hepatotoxicity
Dexfenfluramine anorectic cardiovascular toxFelbamate anticonvulsant aplastic anemia
Flosequinan vasodilator increased mortality
Grepafloxacin antibiotic proarrhythmic
Mibefradil Ca channel blocker serious drug intxnsTemafloxacin antibiotic severe ADR
Terfenadine antihistamine serious drug intxn
Travafloxacin antibiotic hepatotoxicity
Source:J Clin Pharmacol40:1093, 2000
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I. GENERAL CONSIDERATIONSI. GENERAL CONSIDERATIONS
A. CONCEPT OF A THERAPEUTIC WINDOWA. CONCEPT OF A THERAPEUTIC WINDOW
ToxicityDesired
log Concentration
Probability o f
Response
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B. EPIDEMIOLOGICAL CONSIDERATIONSB. EPIDEMIOLOGICAL CONSIDERATIONS
HOSPITALIZED PATIENTS EXPERIENCING ANHOSPITALIZED PATIENTS EXPERIENCING ANADVERSE REACTIONADVERSE REACTION
Drug Class % Pts with Reaction
Antihypertensives 12
Anticoagulants 11Antimicrobials 6
Antiarrhythmics 4
Antiinflammatory 3
Diuretics 3Analgesics 2
Data from: May FE et,al. Drug interactions and multiple drug administration. Clin
Pharmacol Ther22:323, 1977.
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B. EPIDEMIOLOGICAL CONSIDERATIONSB. EPIDEMIOLOGICAL CONSIDERATIONS
Effect of the Number of Drugs a Patient Receives onEffect of the Number of Drugs a Patient Receives onthe Frequency of Adverse Drug Reactionsthe Frequency of Adverse Drug Reactions
Number Antihypertensives Anticoagulants
0-5 9 7
6-10 9 811-15 18 15
16-20 23 18
Data from: May FE et,al. Drug interactions and multiple drug administration. Clin
Pharmacol Ther22:323, 1977.
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B. EPIDEMIOLOGICAL CONSIDERATIONSB. EPIDEMIOLOGICAL CONSIDERATIONS
Prospective study of 237 patients treated with warfarinProspective study of 237 patients treated with warfarinanalyzed for determination of whether or not a druganalyzed for determination of whether or not a drug
interaction occurred with concurrent chloral hydrateinteraction occurred with concurrent chloral hydrate
All patients who received chloral hydrate 237
during warfarin therapy
Those patients who received chloral hydrate
for at least 3 consecutive days 69
Impossible to evaluate (unstable/change therapy) 28
Potentiation of anticoagulant action 22No observable interaction 19
Data from: Koch-Weser J. Hemorrhagic reactions and drug interactions in 500 warfarin
treated patients. Clin Pharmacol Ther14:139-146, 1973.
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C. TYPE OF INTERACTIONC. TYPE OF INTERACTION
UnidirectionalUnidirectional
A B
BidirectionalBidirectional
A B
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D. CLASSIFICATION OF MECHANISMD. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTIONALTERATIONS IN ABSORPTIONComplexation/ChelationComplexation/Chelation
Altered GI TransitAltered GI Transit
Example: anticholinergics + acetaminophenExample: anticholinergics + acetaminophen
Impact: delay in absorption of acetaminophenImpact: delay in absorption of acetaminophen
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D. CLASSIFICATION OF MECHANISMD. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTIONALTERATIONS IN ABSORPTIONComplexation/ChelationComplexation/Chelation
Altered GI TransitAltered GI Transit
Altered Gastric pHAltered Gastric pH
Example: H-2 blockers + ketoconazoleExample: H-2 blockers + ketoconazole
Impact: dissolution of ketoconazole isImpact: dissolution of ketoconazole isdecreased, resulting in reduceddecreased, resulting in reduced
absorptionabsorption
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D. CLASSIFICATION OF MECHANISMD. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTIONALTERATIONS IN ABSORPTIONALTERATIONS IN HEPATIC METABOLISMALTERATIONS IN HEPATIC METABOLISM
Induction of MetabolismInduction of Metabolism
Example: phenobarbital + warfarinExample: phenobarbital + warfarin
Impact: phenobarbital increases theImpact: phenobarbital increases the
metabolism of warfarin, resulting inmetabolism of warfarin, resulting in
reduced anticoagulationreduced anticoagulation
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D. CLASSIFICATION OF MECHANISMD. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTIONALTERATIONS IN ABSORPTIONALTERATIONS IN HEPATIC METABOLISMALTERATIONS IN HEPATIC METABOLISM
Induction of MetabolismInduction of Metabolism
Inhibition of MetabolismInhibition of Metabolism
Example: cimetidine + theophyllineExample: cimetidine + theophylline
Impact: cimetidine reduces the clearanceImpact: cimetidine reduces the clearanceof theophylline causing an increase inof theophylline causing an increase in
adverse effectsadverse effects
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D. CLASSIFICATION OF MECHANISMD. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTIONALTERATIONS IN ABSORPTIONALTERATIONS IN HEPATIC METABOLISMALTERATIONS IN HEPATIC METABOLISM
ALTERATIONS IN RENAL CLEARANCEALTERATIONS IN RENAL CLEARANCE
Increase in Renal Blood FlowIncrease in Renal Blood Flow
Example: hydralazine + digoxinExample: hydralazine + digoxin
Impact: hydralazine increases the renalImpact: hydralazine increases the renal
clearance of digoxinclearance of digoxin
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D. CLASSIFICATION OF MECHANISMD. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTIONALTERATIONS IN ABSORPTIONALTERATIONS IN HEPATIC METABOLISMALTERATIONS IN HEPATIC METABOLISM
ALTERATIONS IN RENAL CLEARANCEALTERATIONS IN RENAL CLEARANCE
Increase in Renal Blood FlowIncrease in Renal Blood Flow
Inhibition of Active Tubular SecretionInhibition of Active Tubular Secretion
Example: probenecid + penicillinExample: probenecid + penicillin
Impact: probenecid prolongs the half-lifeImpact: probenecid prolongs the half-life
of penicillin, allowing single dose therapyof penicillin, allowing single dose therapy
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D. CLASSIFICATION OF MECHANISMD. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTIONALTERATIONS IN ABSORPTIONALTERATIONS IN HEPATIC METABOLISMALTERATIONS IN HEPATIC METABOLISM
ALTERATIONS IN RENAL CLEARANCEALTERATIONS IN RENAL CLEARANCE
Increase in Renal Blood FlowIncrease in Renal Blood Flow
Inhibition of Active Tubular SecretionInhibition of Active Tubular Secretion
Alterations in Tubular ReabsorptionAlterations in Tubular Reabsorption
Example: antacids + aspirinExample: antacids + aspirin
Impact: antacids reduce the tubularImpact: antacids reduce the tubularreabsorption of salicylate via an increasereabsorption of salicylate via an increase
in urine pHin urine pH
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D. CLASSIFICATION OF MECHANISMD. CLASSIFICATION OF MECHANISM
ALTERATIONS IN ABSORPTIONALTERATIONS IN ABSORPTIONALTERATIONS IN HEPATIC METABOLISMALTERATIONS IN HEPATIC METABOLISM
ALTERATIONS IN RENAL CLEARANCEALTERATIONS IN RENAL CLEARANCE
ALTERATIONS IN PLASMA PROTEINALTERATIONS IN PLASMA PROTEIN
BINDINGBINDING
Example: phenytoin + valproic acidExample: phenytoin + valproic acid
Impact: protein binding of valproic acid isImpact: protein binding of valproic acid is
reduced and total Css decreasedreduced and total Css decreased
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COMPOUNDS DEMONSTRATEDCOMPOUNDS DEMONSTRATED
TO BIND WITH IRONTO BIND WITH IRONACETAMINOPHENACETAMINOPHEN MINOXIDILMINOXIDIL
AMPICILLINAMPICILLIN NALIDIXI ACIDNALIDIXI ACID
CAPTOPRILCAPTOPRIL NORFLOXACINNORFLOXACIN
CARBIDOPACARBIDOPA PENICILLAMINEPENICILLAMINE
CIPROFLOXACINCIPROFLOXACIN RIFAMPINRIFAMPIN
ETHAMBUTOLETHAMBUTOL TETRACYCLINETETRACYCLINE
FOLIC ACIDFOLIC ACID THYROXINETHYROXINE
INDOMETHACININDOMETHACIN SALICYLIC ACIDSALICYLIC ACIDLEVODOPALEVODOPA
METHYLDOPAMETHYLDOPA
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B. Mediated by alterations in gastric emptyingB. Mediated by alterations in gastric emptying
or gastrointestinal transitor gastrointestinal transit
1
2
3
4
5
6
7
8
9
10
11
Fasting Fed
GRT
(hr)
Effect of food onEffect of food on
gastric residence timegastric residence time
(GRT) of the(GRT) of the
Heidelberg capsuleHeidelberg capsule
administered toadministered tohealthy male (circles)healthy male (circles)
and female (squares).and female (squares).Reproduced from: MojaverianReproduced from: Mojaverian
P et al. Effect of food on theP et al. Effect of food on the
absorption of enteric coatedabsorption of enteric coated
aspirin: Correlation withaspirin: Correlation with
gastric residence time.gastric residence time. ClinClin
Pharmacol TherPharmacol Ther 41:11-17,41:11-17,
1987.1987.
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Reproduced from: Rowland M,Tozer TN.Reproduced from: Rowland M,Tozer TN. Clinical Pharmacokinetics Concepts and ApplicationsClinical Pharmacokinetics Concepts and Applications, 3, 3rdrd edition,edition,
1995, p.2711995, p.271
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Effect of sumatriptan on acetaminophenEffect of sumatriptan on acetaminophen
absorption in patients with migrainesabsorption in patients with migraines
ParameterParameter APAP aloneAPAP alone with Sumatriptan p valuewith Sumatriptan p value
CCmaxmax (mg/L)(mg/L) 36.3 (10.9)36.3 (10.9) 18.3 (6.7)18.3 (6.7) 0.0010.001
ttmaxmax
(hr)(hr) 1.4 (0.4)1.4 (0.4) 2.7 (1.0)2.7 (1.0) 0.0010.001
tt1/21/2 (hr)(hr) 2.3 (0.7)2.3 (0.7) 3.0 (1.4)3.0 (1.4) NSNS
AUCAUC0-1.50-1.5 26.9 (9.5) 11.8 (3.7)26.9 (9.5) 11.8 (3.7) 0.0010.001
AUCAUC0-30-3 62.3 (14) 33.1 (12.9)62.3 (14) 33.1 (12.9) 0.0010.001
AUCAUC0-80-8 109 (37) 78.8 (31.3)109 (37) 78.8 (31.3) NSNS
Data from: Rani PU, et al. Sumatriptan delays paracetamolData from: Rani PU, et al. Sumatriptan delays paracetamol
absorption in migraine patients.absorption in migraine patients. Clin PharmacokinetClin Pharmacokinet11:300-11:300-
304, 1996.304, 1996.
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III. ALTERATIONS IN DRUG METABOLISMIII. ALTERATIONS IN DRUG METABOLISM
A. InductionA. Induction
int
int
int
uub
O
uubH
uubH
H
CLf
DoseF
AUC
CLfQ
CLfQCL
=
+
=
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Effect of phenobarbital (60 mg qd) on dicumarol plasma concentrations andEffect of phenobarbital (60 mg qd) on dicumarol plasma concentrations and
prothrombin time.prothrombin time. From: Cucinell SA, et al. Lowering effect of phenobarbital on plasma levelsFrom: Cucinell SA, et al. Lowering effect of phenobarbital on plasma levels
of dicumarol and diphenylhydantion.of dicumarol and diphenylhydantion. Clinical Pharmacology & TherapeuticsClinical Pharmacology & Therapeutics 6:420-429, 1965.6:420-429, 1965.
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Reproduced from: Twum-Barima Y, Carruthers SG. Quinidine-rifampin interaction.Reproduced from: Twum-Barima Y, Carruthers SG. Quinidine-rifampin interaction.NEJMNEJM304:1466, 1981.304:1466, 1981.
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From: Rowland M, Tozer TN. Ibid. p. 282.From: Rowland M, Tozer TN. Ibid. p. 282.
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Effect of cimetidine on the clearance on diazepam (D),Effect of cimetidine on the clearance on diazepam (D),
desmethyldiazepam (DZD), chlordiazepoxide (CZD) anddesmethyldiazepam (DZD), chlordiazepoxide (CZD) and
oxazepam (OXM). CZD values are x10, while OXM values areoxazepam (OXM). CZD values are x10, while OXM values are
1/10.1/10.Data from: Somogyi A, Gugler R: Drug interactions with cimetidine.Data from: Somogyi A, Gugler R: Drug interactions with cimetidine. ClinClinPharmacokinetPharmacokinet7:23, 1982.7:23, 1982.
B. InhibitionB. Inhibition
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Summary of studies assessing effect of quinolones on theophyllineSummary of studies assessing effect of quinolones on theophylline
clearance. Data from: Edwards DJ, Bowles SK, Svensson CK, Rybakclearance. Data from: Edwards DJ, Bowles SK, Svensson CK, Rybak
MJ.MJ. Clin PharmacokinetClin Pharmacokinet 15:194, 1988.15:194, 1988.
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FACTORS WHICH ALTER HEPATIC BLOOD FLOWFACTORS WHICH ALTER HEPATIC BLOOD FLOW
Increased FlowIncreased FlowGlucagonGlucagonIsoproterenolIsoproterenolPhentolaminePhentolaminePhenobarbitalPhenobarbital
PGEPGESupine postureSupine postureHigh-protein mealHigh-protein mealViral hepatitisViral hepatitis
Decreased FlowDecreased FlowPropranololPropranololNorepinephrineNorepinephrineAnestheticsAnestheticsLabetalolLabetalol
Upright postureUpright postureHypovolemiaHypovolemiaCHFCHFcirrhosiscirrhosis
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Effect of changing posture on liverEffect of changing posture on liver
blood flow and lidocaine clearanceblood flow and lidocaine clearance
ParameterParameter SupineSupine Sitting/tiltedSitting/tilted
QQHH (mL/min)(mL/min) 1100 (167)1100 (167) 765 (106)765 (106)
CL (mL/min)CL (mL/min) 602 (101) 475 (109)602 (101) 475 (109)
Data presented as mean (SD)Data presented as mean (SD)From: Feely J, et al. Effect of hypotension on liver blood flow and lidocaineFrom: Feely J, et al. Effect of hypotension on liver blood flow and lidocaine
disposition.disposition.N Engl J MedN Engl J Med307:866-869, 1982.307:866-869, 1982.
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V. ALTERATIONS IN RENAL CLEARANCEV. ALTERATIONS IN RENAL CLEARANCE
A. Renal Blood FlowA. Renal Blood Flow
Effect of vasodilators on hemodynamics, renal function and digoxin renalEffect of vasodilators on hemodynamics, renal function and digoxin renal
excretion. CI - cardiac index,; PAH -excretion. CI - cardiac index,; PAH -pp-aminohippuric acid clearance; RBF-aminohippuric acid clearance; RBF
-renal blood flow; and Dig CLr - digoxin renal clearance. Data from Cogan JJ, et-renal blood flow; and Dig CLr - digoxin renal clearance. Data from Cogan JJ, et
al.al. CirculationCirculation 64:973, 1981.64:973, 1981.
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B. Active Tubular SecretionB. Active Tubular Secretion
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B. Urine pHB. Urine pH
Renal clearance of salicylate in 11 yo child with rheumatic fever treatedRenal clearance of salicylate in 11 yo child with rheumatic fever treated
with an antacid. Data from Levy G, Lampman T, Kamath BL,with an antacid. Data from Levy G, Lampman T, Kamath BL,
Garrettson LK. Decreased serum salicylate concentrations in childrenGarrettson LK. Decreased serum salicylate concentrations in children
with rheumatic fever treated with antacid.with rheumatic fever treated with antacid. N Engl J MedN Engl J Med 293:323-325,293:323-325,
1975.1975.
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VI. ALTERATIONS IN PROTEIN BINDINGVI. ALTERATIONS IN PROTEIN BINDING
From: Rowland M, Tozer TN. Ibid, p. 274.From: Rowland M, Tozer TN. Ibid, p. 274.
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Reproduced from: Rowland M, Tozer TN.Reproduced from: Rowland M, Tozer TN.
Ibid, p. 280Ibid, p. 280
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