MS STUDENTS: QUESTIONS TO KNOW SECTION

Flurbiprofen

misspelled!

PROCESSES OF ELIMINATION AND CLEARANCE

Lecture #9

CYP = Cytochrome P450UDPG = UDP glucuronosyltransferase

5

Pathways of Drug Metabolism

Oxidation and Reduction

Conjugation

Drugs

6

Phase I versus Phase II?

A

B

C

D

7

Functions

• Good – Drug Clearance– Toxin Removal*– Homeostasis and Regulation*– Prodrug (inactive) Active Drug*

• Bad- Reduced Efficacy- Increased Toxicity*

8

Functions: Toxin Removalbisphenol A

SulfonationGlucuronidation

9

Functions: Homeostasis and Regulation

10

Functions: Prodrug Drug

Antidepressant

Antihistamine

(Fura et al., 2004)

Antihistamine

Analgesic

11

Functions: Increased Toxicity

Toxic Pathway

Abundance

Contributions

Elimination Rate

Example Midazolam:

Dose = 7.5 mgCL = 28 L/hrV = 140 L

CV=A/V = 7.5 mg/140 L = 0.05 mg/L

Rate of Elimination (mg/hr) = 28 L/hr * 0.05 mg/L = 1.4 mg/hr

Extraction Rate and Extraction Ratio

=1

=E

Extraction Rate

Units = mg/hr

Fraction Remaining

Q*

Q*

Q*

Extraction Ratio

Units = Unitless

Clearance

Units= L/hr

Clearance

Kidneys

Liver

Blood Flow (Q)QH=QR=1 L/hr/kgQH=QR=70 L/hr

Clearance

• Organ– Hepatic (liver)– Renal (kidneys)– Pulmonary (lungs)

• Process– renal/extrarenal– metabolic and excretory clearance

• Site of Measurement– reference fluid (blood vs. plasma clearance)

Additivity of Clearance

Rate ofElimination

Rate ofRenal

Excretion

Rate ofHepatic

Metabolism

Rate ofBiliary

Excretion

Rate ofOther

= + + +

25% 6%69% <1%

Not ShownOn Pie Chart

CYP = cytochrome P450UDP = UDP glucuronsyltransferases

Additivity of Clearance

Rate ofElimination

Rate ofRenal

Excretion

Rate ofHepatic

Metabolism

Rate ofBiliary

Excretion

Rate ofOther

= + + +

25% 6%69% <1%

Additivity of Clearance

Rate ofElimination

Rate ofRenal

Excretion

Rate ofHepatic

Metabolism

Rate ofBiliary

Excretion

Rate ofOther

= + + +

25% 6%69% <1%

CV CV CVCV

CV

~6%

Elimination Rate

System Circulation

Elimination rate

CVCu

Cblood

Assumption: Rapid equilibria between blood, plasma, bound and unbound.

Plasma versus Blood Clearance

Binding of drugs to drug-binding proteins in the plasma.

Binding to blood cells extensive.

= 0.3 to 2.0

Plasma versus Blood ClearanceDrug CV, µM Cblood, µM CV/Cblood

Indomethacin 24 37 0.65

Loperamide 1.03 0.91 1.13

Moxalaction 7.50 12 0.63http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949109/pdf/jcbfm2009200a.pdf

Drug CV/Cblood

Amytriptyline 1.13

Imipramine 1.17

Nortriptyline 1.67

Maprotiline 2.23

Nomifensine 1.21

Diazepam 0.71http://www.clinchem.org/content/26/11/1624.full.pdf

Plasma versus Blood Clearance

Example Verapamil:Plasma/Blood ratio = 1.29CL = 9 L/hr/kgV = 4.3 L/kgA = 0.142 mg/kg

CL = 630 L/hrV= 301 LA= 10 mg

Calculate CV

CV=A/V=10 mg/301 L = 0.033 mg/L

Calculate Cblood

Plasma/Blood ratio=1.29=(0.033 mg/L)/Cblood

Cblood= 0.026 mg/L

Calculate CLblood

CLblood =CL*(CV/Cblood)CLblood =630 * 1.29CLblood = 812.7 L/hr

Total (CL) versus Unbound Clearance (CLU)

CL = 0.26 L/hr/kgCL = 18.2 L/hr (70 kg)fu = 0.048 (i.e. ~95% bound)CLU=18.2/0.048CLU=379 L/hr!

tyrosine kinase inhibitor (anti-cancer)