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METABOLITE KINETICS

 

(a) Acute Metabolites and “Pro-drugs”:

Representative therapeutically important metabolites

Compound Administered	Metabolite
Acetohexamide	Hydroxyhexamide
Acetylsalicylic acid	Salicylic acid
Amitriptyline	Nortriptyline
Chloral hydrate	Trichloroethanol
Chlordiazepoxide	Desmethylchlordiazepoxide
Codeine	Morphine
Diazepam	Desmethyldiazepam
Fluazepam	Desethylfuazepam
Glutethimide	4-Hydroxyglutethimide
Imipramine	Desipramine
Lidocaine	Desethyllidocaine
Meperidine	Normeperidine
Phenacetin	Acetaminophen
Phenylbutazone	Oxyphenbutazone
Prednisolone	Prednisolone
Primidone	Phenobarbital
Procainamide	N-Acetylprocainamide
Propranolol	4-Hydroxypropranolol

(b) Pharmacokinetic model of metabolite formation and elimination:

Rate of change of metabolite

=

Rate of formation

=

Rate of elimination

 

d A(m)	=	km . A	-	k(m) . A(m)
_________
dt
			.
	=	fm . k . A	-	k(m) . A(m)

OR

Vd(m) . dC(m)	=	fm. k . Vd . C	-	k(m) . Vd(m) . C(m)
______________
dt
		.
	=	fm . Cl . C	-	Cl(m) . C(m)
	.
	=	Clm . C	-	Cl(m) . C(m)

Ie. The plasma level - time profile for the metabolite is governed by the relative rates of its formation from the parent drug and its elimination.

(b) Two Limiting Cases:

(i) k << k(m) “formation - rate limited”:

Metabolite is eliminated much more rapidly than parent drug (k is rate limiting).

NB: Same slope (- k / 2.303)

Semilogarithmic plots of the peak height ratios of trichloroethanol () and trichloroethanol glucuronide () with time in a normal dog after intravenous administration of 60mg/kg trichloroethanol. A peak height ratio of 1.0 is equivalent to 8.4mg trichloroethanol or 18.3mg trichjloroethanol glucuronide per millilitre of whole blood. (From Ref. 7).

(ii) k >> k(m) “elimination rate limited”:

Metabolite is eliminated much more slowly than parent drug (uncommon); k(m) is rate - limiting.

NB Slopes are unequal

Most drugs fall between the two extremes.

Integration of previous equation is:-

Vd(m) . dC(m)	=	fm . Cl . C	-	Cl(m) . C(m)
_____________
dt

Yields:-

0 = fm . Cl . AUC - Cl(m) . AUC(m)

AUC(m)		fm . Cl
_________	=	_______
AUC		Cl(m)

(c) “First pass” (hepatic extraction) Consideration:

Eg. Propranolol.

Which is IV/PO?

 

1. If a drug metabolite decays in plasma more slowly than does its precursor:-

(a) Its decay is limited by is formation and nothing else

(b) its decay is a function of its own elimination rate constant, which will be the same if it is administered in its own right

(c) it must be more protein bound than its precursor

(d) it must have a higher volume of distribution than its precursor

(e) its metabolism must be inhibited by the precursor.

 

2. A drug (100mg) is dosed to a 70kg male patient by rapid IV injection. The drug does not bind to plasma proteins, distributes into a volume equivalent to that of blood, and has a plasma clearance of 50mL/min. The drug is cleared from the body as unchanged drug and as one metabolite. Both compounds are voided quantitatively into the urine. A sigma-minus plot of metabolite in urine data yielded a rate constant of 0.2hr-1 and total urinary excretion of metabolite accounted for 25% of the dose.

Calculate the following rate constants:-

a) Urinary excretion rate constant of the parent drug (ku or ke)

(b) metabolic rate constant of the parent drug (km)

(c) total elimination rate constant of the metabolite.

3. 

(a) A drug, which gives rise to a single metabolite that is excreted in urine, has an elimination half-life of 4 hours. When the metabolite is administered alone, a half-life of 2 hours results. What would the observed half-life of the metabolite be if measured following administration of the parent drug, and why?

(b) Equal quantities of two different drugs are administered to a patient by rapid intravenous injection. Neither drug binds to proteins. The concentration of drug A in plasma immediately after dosing is 10mg/L, and the concentration of B is 20mg/L. Drug A has an elimination half-life twice that of drug B. Which drug has the greater plasma clearance, and why?