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Upcoming Exams. Tuesday March 11, 4:30-7:30, Rm 257 Remediation/Make-up Exam 1 Thursday March 13, 4:30-7:30, Rm 257 Remediation/Make-up Exam 2 Tuesday, March 18, 9:30-11:18, Rms 103 & 107 Exam 3. Dosing Regimen Individualization. Drug Interactions Absorption Distribution Elimination. - PowerPoint PPT Presentation


  • Upcoming ExamsTuesday March 11, 4:30-7:30, Rm 257Remediation/Make-up Exam 1Thursday March 13, 4:30-7:30, Rm 257Remediation/Make-up Exam 2Tuesday, March 18, 9:30-11:18, Rms 103 & 107Exam 3

  • Dosing Regimen IndividualizationDrug InteractionsAbsorptionDistributionElimination

  • Drug InteractionsAbsorption: ka and FABBindingMotilityDistribution: VDisplacement - fupElimination: CLDisplacement fupMetabolism induction, inhibition CLint,uHemodynamic QHpHurine

  • Introductory PointsInteractions are graded.Many are too small to affect therapy.Therapeutic Drug Interaction: when there is diminished therapeutic efficacy.Detection (observation) most likely when interacting drug is initiated or withdrawn.Usually unidirectional, rarely bi-directional.

  • Time CourseManifestation of an interaction (e.g., elevated or depressed plasma concentration of drug) may require a relatively long time.2nd Drug CLint,u via inductionCss,avTime1 weeksubtherapeutic

  • Pharmacokinetic vs. PharmacodynamicPhysical InteractionsPhysiological ChangeQHGI MotilityfupAltered primary PKkaFVCLRCLHCompetition for receptors

  • Absorption: ka & FABBinding: adsorbent such as kaolin-pectin mixture or bile-acid sequesterants may reduce both ka and FAB.MJ Malloy et al. Int. J. Clin. Pharmacol. Therap. 35:250, 1997; 32:286, 1994.

    Six healthy volunteers, 3-way cross-over study design. AUC [mg hr L-1]Valproic Acid250 mgSulindac400mgControl489 15331.7 7.944 g cholestyramine coadministered415 113*7.11 3.25*4 g cholestyramine 3 hr later455 12317.88 3.69*

  • Valproic AcidSulindacEHC

  • Mean SD of 6 subjects; *significantly different from control and cholestipol (p < 0.05 )M.A. Al-Meshal, et al. Biopharm. & Drug Disposition 15:463-471,1994.

    Ibuprofin 400 mg p.o.Control A10 g cholestipol B8 g cholestyramine CCmax [mg/L]24.5 1.221.2 2.316.1 1.6*Tmax [h]1.25 0.271.42 0.202.25 0.69*AUC [mg h /L]83.6 2.182.6 5.961.9 14.8*MRT [h]3.8 0.23.8 0.34.5 0.6*t1/2 [h]2.15 0.342.16 0.232.22 0.18

  • S.R. Al-Balla et al. Int. J. Clin. Pharmacol. Therap. 32:441-445,1994.Discrepancy in Tmax and Cmax values between table and figure result from fig. showing average plasma concentrations and table showing the average of the individual Tmax and Cmax values.

    n = 6 SEMmeans with the same letter in the same row are not differentDiclofenac 100 mg p.o.Control A10 g cholestipol B8 g cholestyramine CCmax [ng/mL]3360 199a1416 51b839 75cTmax [h]2.0 0.20a4.3 0.7b5.7 0.6bAUC [ng h / mL]4197 486a2813 222b1605 225c

  • GI MotilityTransit Release: disintegration, dissolutionPermeationstomachPrimary site of absorption is the small intestine.Sm. Intestinal Transit Time is about 3 hr.3 hr

  • Gastric Emptying RateImportant determinant of rate of absorption, particularly when the drug is rapidly absorbed from the small intestine.PEG 4000sulfanilamideME Brady et al. J. Pharm. Sci. 66:366-370,1977.

  • Gastric Emptying RateExamples:Glass of water. Vo = 350 mL, K = 0, t50% = 4.5 min.Beverage, 200 Cal. Vo = 350 mL, K = 0.571 Kcal per mL, t50% = 30 min.Meal, 800 Cal. Vo = 600 mL, K = 1.33 Kcal/mL, t50% = 108 min.

  • Gastric Emptying Rate

    Drugs that slow gastric emptying and intestinal transit:Drugs that speed up gastric emptying and intestinal transit:antimuscurinc drugsanticholinesterases such as parathion and physostigminesedatives and hypnoticsalcoholic beveragesparasympathomimetics such as carbachol, pilocarpine;metoclopramide, lidocaine, procainecaffeinetricyclic antidepressantsAluminum-containing antacidsnicotine (smoking, chewing tobacco)

  • Effects of Reduced Motility on Drug Absorption

    Drug ClasskaFABWell absorbed; lots of intestinal reservePoorly absorbed due to low mucosal permeabilityPoorly absorbed and absorption augmented by active transport Poorly absorbed due to slow dissolution.

  • Well Absorbed; acetaminophenPoorly Absorbed, transporter; riboflavinpropantheline

  • Poorly absorbed due to slow dissolution; digoxin TabletsSolution

  • Impacts: What to do with DR?kahas no effect on Css; peaks and troughs are modulated. No change in DR necessary.FABcauses proportional changes in Css and proportional change in DR is required.

  • DISPLACEMENT: reduction in drug bindingMechanismsCompetition for same site with another drug or substance, the displacerAllosteric mechanism; second drug induces conformation change in binding site. May result in increased as well as decreased binding.For competitive displacement to cause a therapeutic drug interaction:displaced drug must be highly bound (>95%).[displacer] > [binding sites]

  • Binding Sites: macromoleculesAlbuminInvolved in binding of most bound drugs.6 major binding sites per molecule.High plasma concentration: 600 MAcidic drugs are prominently bound, two sites:

    Site 1Site 2Both Siteschlorothiazidebenzodiazepinesindomethacinvalproatepenicillinstolbutamidewarfarinprobenecid

  • Binding Sites: macromolecules1 acid glycoprotein1 binding site per molecule.Low plasma concentration: 10-40 MBasic drugs are prominently boundAcute stress protein; concentration in plasma can rise markedly after surgery, burn, etc.ImmunoglobulinsPlay no role in drug binding.

  • Binding Sites: formed elementsPlasma lipoproteins: bind fat-soluble drugschylomicrons, VLDL, LDL, HDLelevated after a meal

    DrugCharacteristic% of all plasma bound drug that is bound to lipoproteinProbucolneutral >95%Cyclosporinepolypeptide >70%Nicardipinebasic 40-60Propranololbasic 5-20Diclofenacacidic

  • Binding Sites: formed elementsLeukocytes and Plateletshigh affinity for some drugs but low capacity; i.e., easily saturable.

    Drug% of all plasma bound drug that is bound to leukocytes and plateletsBleomycin 80Chloroquine 70-85Doxorubicin 20Cyclosporine 10-20

  • Binding Sites: formed elementsErythrocytesThree drug binding componentshemoglobin: binds phenothiazines, pentobarbital, phenytoincarbonic anhydrase: binds acetazolamide, and chlorthalidonemembrane: binds chlorpromazine and imipramine

  • Concentration dependence

  • Displacement - fupAcute Events:Cp,total drops rapidly and extensively.Cp,unbound increases rapidly but modestly.Chronic (Plateau) Events: depends on effect on CLCLH - Depends on E and route of administrationall E p.o. and low-E parenteral: no effect high-E parenteral: Css,u directly proportional to fupCLR directly proportional to fup (except high-E ATS)

  • Diminished Unbound CLG.K. Dresser, et al. Clinical Pharmacok. 38:41-57, 2000.

    MechanismsInhibitors of CYP3A4Competitive, rapid onset, and rapidly reversible binding to EnzymeAmprenavir, cyclosporin, diltiazem, itraconazole, indinavir, detoconazole, mibefradil, nefazodone, nelfinavir, ritonavirNoncompetitive, rapid onset, and slowly reversible binding to EnzymeTroleandomycin, erythomycin, clarithromycin, iproniazid, isoniazidIrreversible, rapid onset, mechanism-based (suicide substrate)Chloramphenicol, methoxsalen, phencyclidine, griseofulvin, clorgyline, deprenyl, furafylline, bergamottin

  • When there is first-pass hepatic eliminationWhen elimination involves primarily one enzyme and that enzyme is also responsible for extensive first-pass elimination, very large effects result from inhibition. P-gp inhibition may also be involved.

  • High First-Pass / CYP3A4

    FFP < 10%Astemizole, buspirone, ergotamine, lovastatin, nimodipine, nisoldipine, saquinavir, simvastatin, terfenadine10-30%Estradiol, atorvastatin, felodipine, indinavir, isradipine, nicardipine, nitrendapine, propafenone, tacrolimus

  • Example: Midazolam p.o.FFP = 50%Backman JT et al. Eur. J. Clinical Pharmacology 54:53-58 (1998)

    Day / MidazolamItraconazole (inhibitor) Rifampicin (inducer)1 / 15 mg 9 subjects; midazolam at 13:00, itraconazole at 11:00, rifampicin at 20:008-11200 mg/day p.o.11,15 / 7.5 mg29-33600 mg/day p.o.33,37 / 15 mg

  • controlitra D-15itra D-11rif D-37rif D-33controlitra D-15itra D-11

  • Midazolam PK Parameters

    ControlItraconazoleRifampicinDay:111153337Cmax[ng/mL]69.52021203.413.4AUC[ng h/mL]27717076954.427.1t1/2[h]

  • Other Examples

    HMG-CoA Reductase InhibitorSingle dose studies except amult. doseMean effect, value relative to 1 for controlInhibitorAUCCmaxLovastatinCyclosporina20Diltiazem44Grapefruit juice1512Itraconazole15-2015-20SimvastatinErythromycin63Grapefruit juice169Itraconazole>10>10Verapamil53

  • Other Mechanisms CLint,u Q to clearing organ for high E active tubular secretion pHurine for weak acid, HA pHurine for a weak base, B

  • Elevated Unbound ClearanceInduction Mechanisms for Drug Metabolism EnzymesEnzyme stabilization: ethanol and CYP2E1. Enzyme is destabilized when substrate binds to cyp. When ethanol binds to 2E1, the 2E1 is stabilized, which over time results in an increased amount of 2E1. Initially activity is reduced due to enzyme being occupied (acute effect). After continued exposure, amount of enzyme increases but occupation continues. Activity appears to be similar to baseline (pre-ethanol exposure). When inducer is withdrawn, occupation ceases and activity appears to be elevated.Increased Expression

  • Enzymes subject to inductionU. Fuhr. Clinical Pharmacokinetics 38:493-504, 2000.

    Induction TypeMechanismInduced EnzymesAh-receptor (PAH)Increased ExpressionCYP1A1, CYP1A2, GSTs, UGRs, ALDHsEthanolEnzyme StabilizationCYP2E1Peroxisome proliferatorsIncreased ExpressionCYP4 (involved w/ lipoprotein and fatty acid metabolism)CAR (constitutive androstane receptor)/phenobarbit


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