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 InteractionsAbsorptionDistributionElimination

Drug Interactions

Absorption: ka and FAB

•Binding

•Motility

Distribution: V

•Displacement - fup

Elimination: CL

•Displacement – fup

•Metabolism induction, inhibition – CLint,u

•Hemodynamic – QH

•pHurine

Introductory Points

•Interactions 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•Detection (observation) most likely when interacting drug is initiated or withdrawn.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 Course

Manifestation of an interaction (e.g., elevated or depressed plasma concentration of drug) may require a relatively long time.

2nd Drug CLint,u via inductionCss,a

v

Time

1 week subtherapeutic

Pharmacokinetic vs. Pharmacodynamic

Physical InteractionsPhysiological Change

QH

GI Motility fup

Altered primary PK ka

F V CLR

CLH

Competition for receptors

E

log CpCp

Time

Absorption: ka & FAB

Binding: adsorbent such as kaolin-pectin mixture or bile-acid sequesterants may reduce both ka and FAB.

Six healthy volunteers, 3-way cross-over study design.

AUC [mg hr L-1]

Valproic Acid250 mg

Sulindac400mg

Control 489 ± 153 31.7 ± 7.94

4 g cholestyramine coadministered

415 ± 113* 7.11 ± 3.25*

4 g cholestyramine 3 hr later

455 ± 123 17.88 ± 3.69*

MJ Malloy et al. Int. J. Clin. Pharmacol. Therap. 35:250, 1997; 32:286, 1994.

Valproic Acid

Sulindac

EHC

Ibuprofin 400 mg p.o.

ControlA

10 g cholestipol

B

8 g cholestyramine

C

Cmax [mg/L] 24.5 1.2 21.2 2.3 16.1 1.6*

Tmax [h] 1.25 0.27 1.42 0.20 2.25 0.69*

AUC [mg h /L] 83.6 2.1 82.6 5.9 61.9 14.8*

MRT [h] 3.8 0.2 3.8 0.3 4.5 0.6*

t1/2 [h] 2.15 0.34 2.16 0.23 2.22 0.18

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.

n = 6 SEMmeans with the same letter in the same row are not different

Diclofenac 100 mg p.o.

ControlA

10 g cholestipol

B

8 g cholestyramine

C

Cmax [ng/mL] 3360 199a 1416 51b 839 75c

Tmax [h] 2.0 0.20a 4.3 0.7b 5.7 0.6b

AUC [ng h / mL]

4197 486a 2813 222b 1605 225c

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.

GI Motility

Transit

Release: disintegration, dissolution

Permeation

stom

ac

h

t50% = Vo(0.1797 - 0.167e-K)

min mL K = caloric density, Kcal/mL

Primary 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 4000

sulfanilamide

ME Brady et al. J. Pharm. Sci. 66:366-370,1977.

Gastric Emptying Ratet50% = Vo(0.1797 - 0.167e-K)

min mL K = caloric density, Kcal/mL

Examples:

1. Glass of water. Vo = 350 mL, K = 0, t50% = 4.5 min.

2. Beverage, 200 Cal. Vo = 350 mL, K = 0.571 Kcal

per mL, t50% = 30 min.

3. Meal, 800 Cal. Vo = 600 mL, K = 1.33 Kcal/mL, t50% = 108 min.

Gastric Emptying RateDrugs that slow gastric emptying and intestinal transit:

Drugs that speed up gastric emptying and intestinal transit:

antimuscurinc drugs anticholinesterases such as parathion and physostigminesedatives and hypnotics

alcoholic beverages parasympathomimetics such as carbachol, pilocarpine;metoclopramide, lidocaine, procaine

caffeine

tricyclic antidepressants

Aluminum-containing antacids nicotine (smoking, chewing

tobacco)

Effects of Reduced Motility on Drug Absorption

Drug Class ka FAB

Well absorbed; lots of “intestinal reserve”

Poorly absorbed due to low mucosal permeability

Poorly absorbed and absorption augmented by active transport

Poorly absorbed due to slow dissolution.

Well Absorbed; acetaminophen

Poorly Absorbed, transporter; riboflavin

propantheline

Poorly absorbed due to slow dissolution; digoxin

Tablets Solution

Impacts: What to do with DR?

ka has no effect on Css; peaks and troughs are modulated. No change in DR necessary.

FAB causes proportional changes in Css and proportional change in DR is required.

DISPLACEMENT: reduction in drug binding

Mechanisms

•Competition for same site with another drug or substance, the displacer

•Allosteric mechanism; second drug induces conformation change in binding site. May result in increased as well as decreased binding.

For competitive displacement to cause a therapeutictherapeutic drug interaction:

1. displaced drug must be highly bound (>95%).

2. [displacer] > [binding sites]

Binding Sites: macromolecules

Albumin

•Involved in binding of most bound drugs.

•6 major binding sites per molecule.

•High plasma concentration: 600 M

•Acidic drugs are prominently bound, two sites:

Site 1 Site 2 Both Sites

chlorothiazide benzodiazepines

indomethacin

valproate penicillins tolbutamide

warfarin probenecid

Binding Sites: macromolecules

1 acid glycoprotein

•1 binding site per molecule.

•Low plasma concentration: 10-40 M

•Basic drugs are prominently bound

•Acute stress protein; concentration in plasma can rise markedly after surgery, burn, etc.

Immunoglobulins

Play no role in drug binding.

Binding Sites: formed elements

Plasma lipoproteins: bind fat-soluble drugs

•chylomicrons, VLDL, LDL, HDL

•elevated after a meal

DrugCharacteristic

% of all plasma bound drug that is bound to lipoprotein

Probucol neutral >95%

Cyclosporine polypeptide >70%

Nicardipine basic 40-60

Propranolol basic 5-20

Diclofenac acidic <1

Binding Sites: formed elements

Leukocytes and Platelets

•high affinity for some drugs but low capacity; i.e., easily saturable.

Drug% of all plasma bound drug that is bound to leukocytes

and platelets

Bleomycin 80

Chloroquine 70-85

Doxorubicin 20

Cyclosporine 10-20

Binding Sites: formed elements

Erythrocytes

•Three drug binding components

•hemoglobin: binds phenothiazines, pentobarbital, phenytoin

•carbonic anhydrase: binds acetazolamide, and chlorthalidone

•membrane: binds chlorpromazine and imipramine

Concentration dependence

Displacement - fup

Acute Events:

•Cp,total drops rapidly and extensively.

•Cp,unbound increases rapidly but modestly.

Chronic (Plateau) Events: depends on effect on CL

•CLH - Depends on E and route of administration

•all E p.o. and low-E parenteral: no effect

•high-E parenteral: Css,u directly proportional to fup

•CLR – directly proportional to fup (except high-E ATS)

Diminished Unbound CL

Mechanisms Inhibitors of CYP3A4

Competitive, rapid onset, and rapidly reversible binding to Enzyme

Amprenavir, cyclosporin, diltiazem, itraconazole, indinavir, detoconazole, mibefradil, nefazodone, nelfinavir, ritonavir

Noncompetitive, rapid onset, and slowly reversible binding to Enzyme

Troleandomycin, erythomycin, clarithromycin, iproniazid, isoniazid

Irreversible, rapid onset, mechanism-based (suicide substrate)

Chloramphenicol, methoxsalen, phencyclidine, griseofulvin, clorgyline, deprenyl, furafylline, bergamottin

G.K. Dresser, et al. Clinical Pharmacok. 38:41-57, 2000.

When there is first-pass hepatic elimination

When 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, terfenadine

10-30%

Estradiol, atorvastatin, felodipine, indinavir, isradipine, nicardipine, nitrendapine, propafenone, tacrolimus

Example: Midazolam p.o.FFP = 50%

Day / Midazolam

Itraconazole (inhibitor)

Rifampicin (inducer)

1 / 15 mg 9 subjects; midazolam at 13:00, itraconazole at 11:00, rifampicin at 20:00

8-11 200 mg/day p.o.

11,15 / 7.5 mg

29-33 600 mg/day p.o.

33,37 / 15 mgBackman JT et al. Eur. J. Clinical Pharmacology 54:53-58 (1998)

control itra D-15

itra D-11

rif D-37

rif D-33

control

itra D-15

itra D-11

Control Itraconazole Rifampicin

Day: 1 11 15 33 37

Cmax

[ng/mL]69.5 202 120 3.4 13.4

AUC[ng h/mL]

277 1707 695 4.4 27.1

t1/2

[h]2.7 7.6 4.7 0.55 1.0

Midazolam PK Parameters

Other ExamplesHMG-CoA Reductase Inhibitor

Single dose studies except amult. dose

Mean effect, value relative to 1 for control

Inhibitor AUC Cmax

Lovastatin Cyclosporina 20

Diltiazem 4 4

Grapefruit juice 15 12

Itraconazole 15-20 15-20

Simvastatin Erythromycin 6 3

Grapefruit juice 16 9

Itraconazole >10 >10

Verapamil 5 3

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 Clearance

Induction Mechanisms for Drug Metabolism Enzymes

•Enzyme stabilizationEnzyme 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 Increased Expression

Enzymes subject to induction

Induction Type Mechanism Induced Enzymes

Ah-receptor (PAH)Increased Expression

CYP1A1, CYP1A2, GSTs, UGRs, ALDHs

EthanolEnzyme Stabilization

CYP2E1

Peroxisome proliferators

Increased Expression

CYP4 (involved w/ lipoprotein and fatty acid metabolism)

CAR (constitutive androstane receptor)/phenobarbital

Increased Expression

CYP2B6, CYP2C8, CYP2C9, CYP3A4, CYP1A2, some UGTs

PXR (pregnane X receptor) glucocorticoids, rifampicin

Increased Expression

CYP3A mainly in gut

U. Fuhr. Clinical Pharmacokinetics 38:493-504, 2000.

Dr. Mungall

Therapeutic Drug Monitoring – next three classes.

Lectures are soon available on WebCT site – those taking the early final exam will need to take Dr. Mungall’s third class from the web. He will include that material on the early exam.