dose- and time- dependent pharmacokinetics. causes of dose- or time-dependent kinetics process...
TRANSCRIPT
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DOSE- AND TIME-DOSE- AND TIME-DEPENDENT DEPENDENT
PHARMACOKINETICSPHARMACOKINETICS
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CAUSES OF DOSE- OR TIME-DEPENDENT KINETICSCAUSES OF DOSE- OR TIME-DEPENDENT KINETICS
PROCESSPROCESS EXAMPLEEXAMPLE PARAMETERPARAMETER
Saturable gut wall transport riboflavin FSaturable gut wall metabolism salicylamide FPoor solubility griseofulvin F
Saturable plasma protein binding disopyramide fup
Active tubular secretionActive tubular secretion penicillin Gpenicillin G CLCLRR
Active tubular reabsorptionActive tubular reabsorption ascorbic acidascorbic acid CLCLRR
Alterations in urine pHAlterations in urine pH salicylic acidsalicylic acid CLCLRR
Alterations in urine flowAlterations in urine flow theophyllinetheophylline CLCLRR
NephrotoxicityNephrotoxicity gentamicingentamicin CLCLRR
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CAUSES OF DOSE- OR TIME-DEPENDENT KINETICSCAUSES OF DOSE- OR TIME-DEPENDENT KINETICS
PROCESSPROCESS EXAMPLEEXAMPLE PARAMETERPARAMETER
Capacity-limited metabolism phenytoin CLH
Autoinduction carbamazepine CLH
Co-substrate depletion acetaminophen CLH
Product (metabolite) inhibition phenylbutazone CLH
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I. ABSORPTIONI. ABSORPTIONEffect of dose on riboflavin urinary recovery when given on an empty stomach. Date from: Levy G, Jusko WJ. Factors affecting the absorption of riboflavin in man. J Pharm Sci 55:285-289, 1966.
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Effect of dose on ascorbic acid absorption. Data from Blanchard J et al. Am J Clin Nutr 66:1165-1171, 1997
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Steady-state Vitamin C plasma concentration as a function of dose in 13 Steady-state Vitamin C plasma concentration as a function of dose in 13 female subjects receiving doses from 30 to 2,500 mg. From: Levine M, et al. female subjects receiving doses from 30 to 2,500 mg. From: Levine M, et al. A new recommended dietary allowance of vitamin C for healthy young A new recommended dietary allowance of vitamin C for healthy young women. women. Proc Natl Acad Sci USAProc Natl Acad Sci USA 98:9842-9846, 2001. 98:9842-9846, 2001.
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From: Levine M, et al. A new recommended dietary allowance of vitamin C for healthy From: Levine M, et al. A new recommended dietary allowance of vitamin C for healthy young women. young women. Proc Natl Acad Sci USAProc Natl Acad Sci USA 98:9842-9846, 2001. 98:9842-9846, 2001.
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Reproduced from: Rowland M, Tozet TN. Reproduced from: Rowland M, Tozet TN. Clinical Pharmacokinetics – Concepts and ApplicationsClinical Pharmacokinetics – Concepts and Applications , 3, 3rdrd edition, edition, 1995, p. 397.1995, p. 397.
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Reproduced from: Rowland Reproduced from: Rowland M, Tozer TN. Ibid, p. 396.M, Tozer TN. Ibid, p. 396.
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II. ELIMINATIONII. ELIMINATION A. CAPACITY-LIMITED ELIMINATIONA. CAPACITY-LIMITED ELIMINATION
1. MATHEMATICAL ANALYSIS1. MATHEMATICAL ANALYSISThese processes can be described via the These processes can be described via the Michaelis-Michaelis-MentenMenten relationship: relationship:
][][][][][21
1
PEESSEkk
kf
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][][][][][21
1
PEESSEkk
kf
][][][ ESEE fT
][][]][[][
211 ESkESkSEkdt
ESdf
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][][]][[][
211 ESkESkSEkdt
ESdf
0dt
d[ES] statesteady at
][][]][[ 211 ESkESkSEk f
])[(]][[ 211 ESkkSEk f
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1
21
][
]][[
k
kk
ES
SE f
kk-1-1 is a dissociation process, whereasis a dissociation process, whereas k+2 k+2 requires the requires the
breaking of bonds; thus, breaking of bonds; thus, kk-1-1>>>>kk+2+2
mf K
k
k
ES
SE
1
1
][
]][[
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][
]][[
ES
SEK fm
Remember that [Remember that [EEff] = [] = [EETT] – [] – [ESES]]
][
]][[
ES
SESEK Tm
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]][[]][[][ SESSEESK Tm
]][[]][[][ SESESESK Tm
]][[)]([ SESKES Tm
)(
]][[][
SK
SEES
m
T
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)(
]][[][
SK
SEES
m
T
The rate of formation of the product is given as:The rate of formation of the product is given as:
22 ][or ][
k
vESvESk
By implication, the maximum rate is given asBy implication, the maximum rate is given as
2
max2max ][or ][
k
VEkEV TT
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][
][2
max
2 SK
SkV
k
v
m
][
][max
SK
SVv
m
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][
][max
CK
CV
dt
dC
m
For most drugs, For most drugs, KKmm >> >>CC. Hence. Hence
mK
CV
dt
dC ][max
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mK
CV
dt
dC ][max
Since Since VmaxVmax and and KmKm are constant for a given drug in a are constant for a given drug in agiven individual, this ratio will be constant. Eliminationgiven individual, this ratio will be constant. Eliminationwill proceed in a first-order fashion.will proceed in a first-order fashion.
Cdt
dC
K
V
m
ere whmax
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Drugs for which Drugs for which KKmm << << C:C:
ethanolethanolsalicylatesalicylatephenytoinphenytoin
Numerous drugs after first-passNumerous drugs after first-pass
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2. Clinical Consequences2. Clinical Consequences a. Relationship btwn dose and Ca. Relationship btwn dose and Cpp
Reproduced from: Tozer TN, Winter ME. Phenytoin, In: Evans WE, Schentag JJ, Jusko WJ, Reproduced from: Tozer TN, Winter ME. Phenytoin, In: Evans WE, Schentag JJ, Jusko WJ, Applied Applied Pharmacokinetics – Principles for Therapeutic Drug Monitoring. 3Pharmacokinetics – Principles for Therapeutic Drug Monitoring. 3 rdrd edition, 1992, edition, 1992, p. 25-12p. 25-12
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b. Relationship btwn dose and time to b. Relationship btwn dose and time to steady-statesteady-state
From: Ibid.From: Ibid.
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c. Relationship btwn dose and AUCc. Relationship btwn dose and AUCoo
0
1
2
3
0 100 200 300 400 500
Oral Dose (mg)
(AU
C (
mcg
-hr/
mL
)
Plasma AUC of Plasma AUC of lorcainide in a subject lorcainide in a subject as a function of dose. as a function of dose. Data from: Janchen E et al. Data from: Janchen E et al. Clin Pharmacol TherClin Pharmacol Ther 26:187, 26:187, 1979.1979.
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c. Relationship btwn dose and AUCc. Relationship btwn dose and AUCoo
0
0.001
0.002
0.003
0.004
0.005
0.006
0 100 200 300 400 500
Oral Dose (mg)
AU
C/D
ose
Plasma AUC/Dose of Plasma AUC/Dose of lorcainide in a subject lorcainide in a subject as a function of dose. as a function of dose. Data from: Janchen E et al. Data from: Janchen E et al. Clin Pharmacol TherClin Pharmacol Ther 26:187, 26:187, 1979.1979.
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d. Relationship btwn dose and d. Relationship btwn dose and bioavailabilitybioavailability
Bioavailability of Bioavailability of nicardipine after oral nicardipine after oral administration. administration. Data Data from: Wagner JG et al. from: Wagner JG et al. Biopharm Drug DisposBiopharm Drug Dispos 8:133- 8:133-148, 1987.148, 1987.
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e. Relationship btwn Cp and timee. Relationship btwn Cp and time
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3. Determination of Michaelis-Menten 3. Determination of Michaelis-Menten ParametersParameters
a. Lineweaver-Burke Expressiona. Lineweaver-Burke Expression
maxmax
max
max
11
1
VCV
K
v
CV
CK
v
CK
CVv
m
m
m
1/1/vv
1/C1/C
1/K1/Kmm
1/V1/Vmaxmax
Slope = KSlope = Kmm/V/Vmaxmax
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b. b. In Vivo DeterminationIn Vivo Determination
ssm
mssss
ssssm
ssssm
ssm
ss
ssm
ss
C
KKVK
KKCVCK
CVCKKK
CVCKK
CK
CVK
K
CK
CVv
0max0
0max0
max00
max0
max0
0
max
)(
)(
rateinput If
KK00
KK00/C/Cssss
VVmaxmax
KKmm
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JB is an 18 yo male receiving phenytoin for prophylaxis JB is an 18 yo male receiving phenytoin for prophylaxis of post-traumatic head injury seizures. The following of post-traumatic head injury seizures. The following steady state concentrations were obtained at the steady state concentrations were obtained at the indicated doses:indicated doses:
Dose (mg/d)Dose (mg/d) Css (mg/L)Css (mg/L) 100100 3.73.7 300300 4747
From this data, determine this patient’s From this data, determine this patient’s KKmm and V and Vmaxmax
for phenytoin.for phenytoin.
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JB is an 18 yo male receiving phenytoin for prophylaxis JB is an 18 yo male receiving phenytoin for prophylaxis of post-traumatic head injury seizures. The following of post-traumatic head injury seizures. The following steady state concentrations were obtained at the steady state concentrations were obtained at the indicated doses:indicated doses:
Dose (mg/d)Dose (mg/d) Css (mg/L)Css (mg/L) Dose Rate/Css (L/d)Dose Rate/Css (L/d) 100100 3.73.7 2727 300300 4747 6.46.4
KK00 (mg/d) (mg/d)
KK00/C/Cssss (L/d) (L/d)
VVmaxmax = 362 mg/d = 362 mg/d
KKmm = 9.7 mg/L = 9.7 mg/L
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What CWhat Cssss would be expected if a dose of 200 mg/d were would be expected if a dose of 200 mg/d were
given to this patient?given to this patient?
LmgC
CLmg
Cdmgdmg
CK
CVK
ss
ss
ss
ssm
ss
/ 12
)/ 7.9(
)/ 362(/ 200
max0
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4. Application to Alcohol4. Application to Alcohol
EthanolAlcohol dehydrogenase
acetaldehyde
Avg Avg VVmaxmax = 10 g/hr = 10 g/hr
KKmm = 100 mg/L = 100 mg/L
Detectable pharmacologic effect: 250 mg/LDetectable pharmacologic effect: 250 mg/LLethal concentrations >7000 mg/LLethal concentrations >7000 mg/L
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Note: EtOH metabolism Note: EtOH metabolism becomes zero-order. becomes zero-order. One jigger (45 mL) of 80 One jigger (45 mL) of 80 proof EtOH contains proof EtOH contains ~14 g of ethanol – which ~14 g of ethanol – which exceeds the exceeds the Vmax!Vmax!
Data from: Rowland M, Tozer TN. Ibid, p. 406.
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Reproduced from: Ibid, p. 408.
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Reproduced from: Ibid, p. 408.Reproduced from: Ibid, p. 408.
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B. AutoinductionB. Autoinduction
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C. Saturable Renal Tubular ReabsorptionC. Saturable Renal Tubular Reabsorption
Steady-state plasma ascorbic acid concentration in healthy adults Steady-state plasma ascorbic acid concentration in healthy adults receiving various regimens twice daily for 3 to 4 weeks. receiving various regimens twice daily for 3 to 4 weeks. Control Control subjects had no supplement. Estimated daily dietary intake of ascorbic acid was 50-subjects had no supplement. Estimated daily dietary intake of ascorbic acid was 50-75 mg. From: 75 mg. From: Nutr Rep InternNutr Rep Intern 30:597-601, 1984. 30:597-601, 1984.
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Reproduced from: Rowland M, Tozer TN. Ibid, p. 404.Reproduced from: Rowland M, Tozer TN. Ibid, p. 404.
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III. SATURABLE PROTEIN BINDINGIII. SATURABLE PROTEIN BINDING
Dose vs AUC for naproxen after single (AUCs) and Dose vs AUC for naproxen after single (AUCs) and multiple (AUCm) doses. multiple (AUCm) doses. From: From: Clin Pharmacol TherClin Pharmacol Ther 15:261-266, 1974. 15:261-266, 1974.
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In vitro In vitro binding of naproxen as a function of Cp.binding of naproxen as a function of Cp.
Naproxen Plasma Concentration (mg/L)
Per
cen
t F
ree
0
1
2
3
0 100 200 300 400 500
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free concentration
total concentration
ER (mg/hr)
Naproxen Concentration
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fu at 2 hr postdose
0.0 0.2 0.4 0.6 0.8 1.0
CL/F
Tot
al, L
/hr
0.0
0.1
0.2
0.3
0.4
0.5
40
80
120
160
200
CL/F
Unbou
nd, L
/hr
Total Drug
Unbound Drug
Relationship between oral clearance and fraction Relationship between oral clearance and fraction unbound of oxaprozin. unbound of oxaprozin. From: From: J Clin PharmacolJ Clin Pharmacol 36:985-997, 1996. 36:985-997, 1996.