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CLINICAL PHARMACOKINETICS OF NSAID’S

1. Introduction:

Widely used group of drugs with multiple actions:-

- Analgesic.

- Anti-inflammatory.

- Antipyretic.

- Antiplatelet.

 

2. Pharmacokinetic Overview:

(a) Absorption:

- Weak acids.

- Well absorbed (> 80%).

- Delayed absorption with food.

- Rate of absorption important when used as occasional analgesic or antipyretic.

- Often enteric-coated (eg. Aspirin, Diclofenac) or film-coated (eg. Diflunisal) to minimise GE side effects. These coatings may also delay absorption and reduce fluctuations in blood levels with chronic dosing.

(b) Distribution:

- Extensively protein bound relatively small volumes of distribution.

- Synovial fluid levels correlate with unbound levels in plasma, although there is less inter-dose fluctuation.

(c) Metabolism:

- NSAID’s are eliminated predominantly by metabolism.

- Generally, oxidation then glucuronidation renal excretion.

- Naproxen, Indomethacin undergo demethylation.

Inter-patient differences in the metabolic clearances (and half-lives) of individual NSAID’s can be large considerable variability in plasma and synovial fluid levels.

- Active metabolites,

Eg. Aspirin Salicylate

Sulindac Sulindac sulphide

Ibuprofen

Fenoprofen

Phenylbutazone

- Saturable metabolism, Salicylate, Diflunisal.

- Enterohepatic cycling, Indomethacin, Sulindac.

- Enterohepatic cycling of Sulindac and reversible metabolic activation maintain plasma levels.

- Kidney is spared to some extent from anti-prostaglandin effects.

- Likewise, upper GIT is spared from the active sulphide (irritant).

- Prolonged effect in liver disease ( biliary excretion).

- Propionates consist of two optical isomers:-

- Naproxen marketed as active S-isomer.

- Others, eg. Ibuprofen, Fenoprofen marketed as racemates : some metabolic inversion from inactive to active isomer occurs.

- metabolism may occur in elderly, eg. Naproxen.

(d) Excretion:

- Small component of the elimination of NSAID’s.

Exception : Salicylate with alkaline urinary pH.

- Renal failure prolongs the half-life of several NSAID’s.

Eg. (Glucuronides hydrolysis to parent drug retained) :

Diflunisal
Indomethacin 
Ketoprofen 
Naproxen

 

TABLE: Pharmacokinetic Parameters of NSAID’s
Drug	Steady-state serum levels (mcg/ml)	Half-life (hr)	% Protein binding	Vd (Litres)¶	Elimination
Fenoprofen	30-45	1.5-3	> 99	5.4-7.5	90% excreted as glucuronides, 1-3% unchanged in urine
Ibuprofen	25-40	2	99	10	12% as glucuronides in urine, 1% unchanged
Indomethacin	0.3-2.0	4-12	92-99	10-13§	Desmethyl, des (chlorobenzoyl) metabolites. 65% excreted in urine, 35% in faeces
Meclofenamic acid	0.5-3.0	3	99.8	?	Oxidation, dehalogenation and conjugation
Naproxen	30-55	12-15	99-99.5	6.3	Desmethyl metabolite. 10% excreted unchanged, 28% as metabolite, 50-60% as conjugates in urine
Oxyphenbutazone	25-100	27-64	97-98	10	Renal excretion
Phenylbutazone	25-100	29-175§	98-99	0.02-0.15¤ litre/kg	Hydroxylation
Sulindac Sulfide (active metabolite)	1--6 2.5-10	7-8 16-18	93 93-98	? ?	75% in urine as Sulindac, sulfone, and conjugates, 25% in faeces as sulfone and sulfide.
Tolmetin	30-55	1¥ 5€	99	7-10¥ 2.5€	In urine, 10% unchanged, 10% as glucuronide, rest as dicarboxylic acid metabolite
¶ Volume of distribution.  § Conflicting data, see text.  ¤ Dose-dependent.  ¥ Assumes non-linear kinetics.  € Assumes linear kinetics.

 

 

TABLE: Half-Lives of Non-Steroidal Anti-Inflammatory Drugs¶
Non-steroidal Anti-inflammatory Drugs	Half-life (h)	Comments
Non-steroidal Anti-inflammatory drugs with short half-lives
Aspirin	0.25 + 0.03	Prolonged effect due to irreversible acetylation and metabolism to Salicylate
Fenoprofen	2.5 + 0.5
Flurbiprofen¶	3.8 + 1.2
Ibuprofen	2.1 + 0.3	Half-life not prolonged by renal or liver failure or in elderly.
Ketoprofen	1.8 + 0.4	Longer half-life in renal failure (3.2 + 0.5 h) and elderly (2.7 + 0.6 h) but half-life still short
Tiaprofenic acid§	3 + 0.2
Diclofenac	1.1 + 0.2	Half-life not prolonged by renal failure or in elderly
Indomethacin	4.6 + 0.7
Pirprofen§	3.8, 6.8
Tolmetin¤	1 + 0.3, 6.8 + 1.5
Etodolac § ¤	3 (approx), 6.5 + 0.3	Half-life not prolonged in elderly
Flufenamic acid¤	1.4, 9
Non-steroidal anti-inflammatory drugs with long half-lives
Salicylate	2-15	Saturable metabolism. Half-life increases with increasing dose and decreases with increasing urinary pH. Disproportionate increase in plasma levels with increasing dose
Diflunisal	13 + 1.5	Longer half-life in renal failure (15-138 h) depending on degree of renal impairment
Fenbufen (active metabolite)§	11
Naproxen	14 + 2	Higher unbound concentrations in elderly
Sulindac (active metabolite)	14 + 8	Slower elimination in liver failure
Oxaprozin§	58 + 10	Half-life not prolonged in elderly
Piroxicam	57 + 22	Half-life increased by approximately 30% in women
Azapropazone§	15 + 4
Phenylbutazone	68 + 25	Active per se but active metabolite (oxyphenbutazone) also accumulates during multiple dosages
Tenoxicam§	60 + 11
¶ Values expressed as mean + standard deviation. Data were obtained from studies in both healthy volunteers and in patients.  § Marketed overseas but not in Australia.  ¤ Biphasic elimination. The first phase is generally the most important.

3. Plasma Levels and Clinical Response:

- Only Salicylate has an optimum plasma level range (150-300mg/ml), although the evidence to support this range is very limited.

- Difficulties in establishing optimum plasma level ranges:-

- Quantification of therapeutic response.
- Marked inter-patient differences in response to different NSAID’s.
- Large fluctuations in plasma levels between doses.

 

4. Drug Interactions:

(i) Pharmacokinetic:

- Inhibition of metabolism of Phenytoin, Warfarin, Tolbutamide by Phenylbutazone.

- renal clearance of Lithium.

- secretion of Methotrexate (esp. Salicylate).

(ii) Pharmacodynamic:

- Inhibition of diuresis.

- Potentiation of anticoagulation.