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•Detection (observation) most likely when interacting drug is initiated or withdrawn.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