Fakhreddin Jamali

Clinical Pharmacokinetics of Ketoprofen and Its Enantiomers

SummaryKetoprofen, a potent nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid class, has been used clinically for over 15 years in Europe, and has recently been introduced in the United States. Although it possesses a chiral centre, with only the S-enantiomer possessing beneficial pharmacological activity, all ketoprofen preparations to date are marketed as the racemate. Ketoprofen exhibits little stereoselectivity in its pharmacokinetics. The enantiomers have similar plasma time-courses and do not seem to interact with one another. Hence, the data generated using nonstereospecific assays may be used to explain the pharmacokinetics of individual enantiomers.The absorption of ketoprofen is rapid and almost complete when given orally. Sustained release dosage forms are available, which may be beneficial due to the short terminal phase half-life of ketoprofen (1 to 3h). They may also decrease local gastrointestinal side effects. Although with these preparations the peak plasma drug concentration is reduced and time to peak is prolonged, the bioavailability is the same as that with regular release counterparts. Ketoprofen binds extensively to plasma albumin, apparently in a stereoselective manner. Substantial concentrations of the drug are attained in synovial fluid, the proposed site of action of NSAIDs. It is eliminated following extensive biotransformation to inactive glucuroconjugated metabolite. There is about 10% R to S inversion upon oral administration. Conjugates are excreted in urine, and virtually no drug is eliminated unchanged. The excretion of conjugates is closely tied to renal function; accumulation of conjugates occurs in the elderly, but not in young subjects or patients. Significant drug interactions have been demonstrated for probenecid, aspirin and methotrexate. There appears to be circadian variation, particularly in the absorption of ketoprofen. The relationship between concentration and anti-inflammatory effect has yet to be elucidated for this drug.

Renal adverse effects of nonsteroidal anti-inflammatory drugs

NSAIDs depress prostaglandins synthesis through inhibition of COX-1 that is involved in maintaining cell integrity and COX-2 that, although presents particularly in the kidneys, is overexpressed in response to inflammation. Both the beneficial and side effects of NSAIDs are, therefore, through their inhibition of COX enzymes. Introduction of COX-2-selective inhibitors has improved the safety profile of the drugs with regard to their most common side effect which occurs at the gastrointestinal level but has not rendered them less cardio-nephrotoxic. Renal side effects of NSAIDs are rare, sometimes transient and often reversible upon drug withdrawal. The incident rate and the severity of the renal side effect, however, increase in patients with risk factors such as those with diabetes, heart failure, renal dysfunction and in the elderly. The side effects range from electrolyte retention and reduce glomerular filtration to nephritic syndrome and chronic renal failure. These effects are shared among NSAIDs with evidence of dose and exposure dependency. There is no known predictor for the nephrotoxicity. However, a relationship has been found between high plasma concentration and the renal adverse effect of NSAIDs. The usefulness of therapeutic drug monitoring in patients with risk factors needs to be explored.

Adverse Effects of Nonsteroidal Antiinflammatory Drugs: An Update of Gastrointestinal, Cardiovascular and Renal Complications

Non-steroidal anti-inflammatory drugs (NSAIDs) are used chronically to reduce pain and inflammation in patients with arthritic conditions, and also acutely as analgesics by many patients. Both therapeutic and adverse effects of NSAIDs are due to inhibition of cyclooxygenase (COX) enzyme. NSAIDs are classified as non-selective and COX-2-selective inhibitors (COXIBS) based on their extent of selectivity for COX inhibition. However, regardless of their COX selectivity, reports are still appearing on the GI side effect of NSAIDs particularly on the lower gastrointestinal (GI) tract and the harmful role of their controlled release formulations. In addition, previously unpublished data stored in the sponsors files, question the GI sparing properties of rofecoxib, a COXIB that has been withdrawn due to cardiovascular (CV) side effects. Presently, the major side effects of NSAIDs are the GI complications, renal disturbances and CV events. There is a tendency to believe that all NSAIDs are associated with renal and CV side effects, a belief that is not supported by solid evidence. Indeed, lower but still therapeutics doses of some NSAIDs may be cardioprotective. In this review, we briefly discuss the GI toxicity of the NSAIDs and assess their renal and CV adverse effects in more detail.

Clinical pharmacokinetics of ketorolac tromethamine.

SummaryKetorolac is a new chiral nonsteroidal anti-inflammatory drug (NSAID) which is marketed for analgesia as the racemate. The drug is administered as the water soluble tromethamine salt and is available in tablets or as an intramuscular injection. The absorption of ketorolac is rapid, Cmax being attained between 20 to 60 min. Its oral bioavailability is estimated to range from 80 to 100%. The drug is extensively bound (>99%) to plasma proteins and has a volume of distribution (0.1 to 0.3 L/kg) comparable with those of other NSAIDs. Only small concentrations of ketorolac are detectable in umbilical vein blood after administration to women in labour. The elimination half-life is between 4 and 6h and is moderate in comparison with other NSAIDs. The area under the plasma concentration-time curve of ketorolac is proportional to the dose after intramuscular administration of therapeutic doses to young healthy volunteers.Ketorolac is extensively metabolised through glucuronidation and oxidation; little if any drug is eliminated unchanged. Most of the dose of ketorolac is recovered in the urine as conjugated drug. Although ketorolac is excreted into the breast milk, the amount of drug transferred comprises only a small fraction of the maternal exposure. Little stereoselectivity was present in the pharmacokinetics of ketorolac in a healthy volunteer receiving single intravenous or oral doses. The elderly exhibit reduced clearance of the drug. Renal insufficiency appears to cause an accumulation of ketorolac in plasma, although hepatic disease may not affect the pharmacokinetics.

Pharmacokinetics of Ibuprofen Enantiomers in Humans Following Oral Administration of Tablets with Different Absorption Rates

Ibuprofen (IB) is a racemic drug and is administered as such. While activity is due mainly to the S enantiomer, pharmacokinetic interpretations, as well as criteria to assess the bioequivalence of IB formulations, are based on measurements of the total (S + R) drug concentrations. IB enantiomers possess different disposition properties mainly as a result of R-to-S isomeric bioinversion. Inversion is maximal during the absorption phase, suggesting, perhaps, involvement of a presystemic process. This concept was evaluated in healthy subjects by crossover administration of four IB tablets having different absorption rates. The plasma concentrations of the individual isomers were measured using a stereospecific gas chromatographic assay. Differences among the products were insignificant with respect to the extent to the absorption. The S:R concentration ratios rose for 4 to 6 hr and then remained relatively unchanged. This observation was consistent with equal terminal t1/2 values for the enantiomers. There were significant differences between the peak times (Tmax) of the products. The S:R ratios of the concentrations at Tmax of S and AUC also differed; significant positive correlations were found between Tmax and the S:R ratios of Cmax. Thus the extent of R-to-S inversion, and hence the potency of a racemic dose of IB, may be absorption rate dependent.

Protective effects of angiotensin II interruption : Evidence for antiinflammatory actions

Angiotensin II, the major effector molecule produced renin‐angiotensin‐aldosterone axis, is a vasoconstrictor contributing to hypertension. Evidence indicates, however, that angiotensin II also is a potent proinflammatory mediator with growth and remodeling effects. In vitro and in vivo studies have shown that angiotensin II blockade significantly reduces concentrations of proinflammatory mediators and oxidative stress products in numerous inflammatory models. Interruption of angiotensin II activity with angiotensin‐converting enzyme inhibitors and angiotensin II receptor blockers has been beneficial for patients with inflammatory diseases. Much of this benefit occurs independent of the antihypertensive effect of angiotensin II interruption, suggesting a distinctive protective mechanism. Angiotensin II receptor blockers may represent a novel class of antiinflammatory drugs with indications far beyond cardiovascular diseases.

High-performance liquid chromatographic analysis of angiotensin II receptor antagonist valsartan using a liquid extraction method.

PURPOSE To develop an easy assay for the quantitation of the angiotensin II receptor antagonist valsartan in human plasma using a liquid extraction procedure. METHOD The method involves acid extraction from 1 ml human plasma with methyl-tert.-butyl ether followed by back-extraction into a basic medium. An isocratic HPLC equipped with reverse phase column and a fluorescence detector was used at room temperature. RESULTS The response to 10-2000 ng/ml valsartan was linear. In plasma of three human subjects given 160 mg valsartan orally, concentrations of 25-1540 ng/ml were observed. CONCLUSION This convenient method is suitable for pharmacokinetic studies of valsartan.

Selective effect of adjuvant arthritis on the disposition of propranolol enantiomers in rats detected using a stereospecific HPLC assay

Nonstereospecific studies have indicated that the pharmacokinetics of propranolol (PR) are altered in inflammatory conditions such as arthritis. However, as the kinetics and dynamics of PR are stereoselective, we examined the effect of adjuvant arthritis (AA) on the disposition of the individual enantiomers. A novel normal-phase stereospecific HPLC assay for PR was developed involving chiral derivatization with S-(naphthyl)ethyl isocyanate and fluorescence detection. Oral and iv doses of racemic PR were administered to control and AA rats (n = 6). AA had no significant effect on either clearance or S:R ratio after iv doses. On the other hand, after oral doses, clearance was significantly decreased in AA. Although significant for both enantiomers, this effect was more pronounced on the less active R-enantiomer. The AUC R:S ratio was, therefore, significantly altered (AA, 14 ± 3.0; control, 4.3 ± 1.2). Increased total (S + R) plasma concentrations of PR in AA, possibly due to a reduced intrinsic clearance, therefore, reflect mainly increased concentrations of the less active R-enantiomer.

Low‐dose methotrexate kinetics in arthritis

Twelve patients with either rheumatoid or psoriatic arthritis were injected with a 10‐mg bolus dose of methotrexate (MTX) either intramuscularly (n = 6) or intravenously (n = 6) and the MTX concentration in their sera was determined by radioimmunoassay. MTX concentration‐time data fitted triexponential equations. Doses injected intramuscularly were rapidly and completely absorbed. There were no significant intergroup differences in drug mean t½, volume of distribution, and total body clearance. In nine patients serum MTX concentrations remained above the suggested critical level of 0.01 µmol throughout the 24‐hr study irrespective of the route of administration, but MTX did not cumulate in the serum. We conclude that the behavior of low doses of MTX in patients with arthritis closely resembles the pattern in patients receiving intermediate and high doses for the treatment of neoplasia.

Drug-disease interactions : reduced β-adrenergic and potassium channel antagonist activities of sotalol in the presence of acute and chronic inflammatory conditions in the rat

Inflammation may influence response to pharmacotherapy. We investigated the effect of inflammation on response to sotalol, a β‐adrenergic receptor and potassium channel antagonist. Racemic sotalol (40 mg kg−1) was administered to healthy, acutely (interferonα 2a‐induced) and chronically (Mycobacterium butyricum‐induced adjuvant arthritis) inflamed male Sprague‐Dawley rats (n=4 – 6/group). Another group of interferon‐treated rats received 3 mg kg−1 of anti‐TNF antibody infliximab. Electrocardiogram (ECG) recorded and plasma sotalol concentration monitored for 6 h. The study was repeated in acutely inflamed rats following administration of stereochemically pure individual sotalol enantiomers [40 mg kg−1 S (potassium channel blocker) or 20 mg kg−1 R (β‐adrenergic/potassium channel blocker)]. Chronic arthritis was readily evident. Acute arthritis was associated with elevated segmented neutrophils and increased plasma nitrite and tumour necrosis factor (TNF) concentrations. Sotalol affected ECG in all rats. In both inflamed groups, however, response to sotalol in prolongation of QT interval (potassium channel sensitivity) was reduced. The effect of PR interval (β‐adrenergic activity) was also reduced following administration of the racemate and R‐enantiomer. No significant differences in pharmacokinetics were observed between control and inflamed rats. Infliximab reduced nitrite and TNF concentrations and reversed the effect of acute inflammation on both PR and QT intervals. The reduced electrocardiographic responses to sotalol is likely due to the influence of inflammation on the action of the drug on both β‐adrenergic and potassium channel receptors secondary to over‐expression of pro‐inflammatory cytokines and/or nitric oxide. Our observation may have therapeutic consequences in all conditions where inflammatory mediators are increased.