Bioavailability and pharmacokinetics of lorazepam after intranasal, intravenous, and intramuscular administration.

The purpose of this study was to evaluate the pharmacokinetic profile of intranasal lorazepam in comparison to currently established administration routes. Eleven healthy volunteers completed this randomized crossover study. On three occasions, each separated by a 1-week washout, subjects received a 2 mg dose of lorazepam via the intranasal, intravenous, or intramuscular route. Blood samples were collected serially from 0 to 36 hours. Noncompartmental methods were used to determine pharmacokinetic parameters. Lorazepam was well absorbed following intranasal administration with a mean (%CV) bioavailability of 77.7(11.1). Intranasal administration resulted in a faster absorption rate than intramuscular administration. Elimination profiles were comparable between all three routes. The concentration-time profile for intranasal delivery demonstrated evidence of a double peak in several subjects, suggesting partial oral absorption. Females were found to have significantly higher AUC values than males for all three delivery routes. Overall, this study demonstrated favorable pharmacokinetics of intranasal lorazepam in relation to standard administration methods. Intranasal delivery could provide an alternative, noninvasive delivery route for lorazepam.

Stereoselective pharmacokinetics and inversion of (R)- ketoprofen in healthy volunteers.

The pharmacokinetics of ketoprofen enantiomers were evaluated after 25-, 50-, and 100-mg doses of (R)- ketoprofen and 100 mg of racemic ketoprofen in 25 healthy volunteers (12 male and 13 female). The fractional inversion (Finv) of (R)- ketoprofen was 8.9 +/- 3.3% using plasma data and 10.0 +/- 2.2% using urine data. There were small (< 5%) but significant differences between the enantiomers for areas under the plasma concentration-time curve (AUC) after the racemic dose (P < 0.005). Half-lives were 130-144 minutes for (R)- ketoprofen and 132-209 minutes for (S)- ketoprofen. Dose proportionality in AUC and maximum plasma concentration (Cmax) values was noted for both enantiomers. A total of 69% of the dose was recovered in the urine as (R)- and (S)- ketoprofen and conjugates. The elimination rate constant of (R)- ketoprofen was significantly different (P < 0.05) between men and women. Exposure to cyclooxygenase inhibiting (S)- ketoprofen was approximately 10% of the dose after the administration of pure (R)- ketoprofen and was independent of gender.

In vivo absorption of aluminium-containing vaccine adjuvants using 26Al.

Aluminium hydroxide (AH) and aluminium phosphate (AP) adjuvants, labelled with 26Al, were injected intramuscularly (i.m.) in New Zealand White rabbits. Blood and urine samples were collected for 28 days and analysed for 26Al using accelerator mass spectrometry to determine the absorption and elimination of AH and AP adjuvants. 26Al was present in the first blood sample (1 h) for both adjuvants. The area under the blood level curve for 28 days indicates that three times more aluminium was absorbed from AP adjuvant than AH adjuvant. The distribution profile of aluminium to tissues was the same for both adjuvants (kidney > spleen > liver > heart > lymph node > brain). This study has demonstrated that in vivo mechanisms are available to eliminate aluminium-containing adjuvants after i.m. administration. In addition, the pharmacokinetic profiles of AH and AP adjuvants are different.

The Influence of Misoprostol on the Adverse Renal Effects and Stereospecific Pharmacokinetics of Ibuprofen in Chronic Renal Insufficiency.

The use of nonsteroidal anti-inflammatory drugs in patients with chronic renal insufficiency (CRI) may be complicated by renal functional abnormalities due to the inhibition of renal prostaglandins. We tested the hypothesis that administration of the oral PGE1 analog, misoprostol, could attenuate the adverse renal effects of ibuprofen in patients with CRI. Because the metabolism of misoprostol and the stereoinversion of R- to S-ibuprofen involve the same metabolic pathway, the stereospecific pharmacokinetics of ibuprofen were also evaluated. In a randomized, crossover trial of six stable CRI patients (Clcr 25--67 ml min(minus sign1)), in sodium balance on a 150 mEq Na(+) per day metabolic diet, we compared the effects of ibuprofen 600 mg qid with and without misoprostol 200 &mgr;g qid upon Clcr, Clinulin, Clpah, Na(+), and K(+) excretion during 4-h clearance studies. We also assessed stereospecific ibuprofen kinetics following single dose (acute) and after 7 days on drug(s) (chronic). Daily weights, supine blood pressures, electrolytes, osmolality, BUN, creatinine and 24-h urine collections for Clcr and Na(+) and K(+) excretions were obtained during chronic dosing. Supine and upright plasma renin activities were obtained prior to dosing and during chronic dosing for both treatment limbs. Ibuprofen alone resulted in an approximately 20% transient reduction in GFR, occurring 2--2.5 h following dosing in both the acute and chronic clearance studies. This was not affected by misoprostol. There was a greater degree of stimulation of PRA with the upright posture with misoprostol plus ibuprofen than with ibuprofen alone. There was a significant weight gain in both study limbs, but no effect of misoprostol (1.2 plus minus 0.2 kg ibuprofen alone and 1.0 plus minus 0.2 kg ibuprofen plus misoprostol, p = 0.13). Otherwise no clinically significant alteration in renal function occurred in either treatment limb. The presence of misoprostol did not alter the stereospecific pharmacokinetics of ibuprofen. We conclude that misoprostol does not significantly alter the renal effects of ibuprofen in patients with mild to moderate CRI.

Enantioselective disposition of ibuprofen in elderly persons with and without renal impairment.

By using stable isotope methodology, we studied the disposition of ibuprofen after the first and last dose of a 4-week regimen of 800 mg of racemic ibuprofen every 8 hr in three groups of subjects: 1) young healthy volunteers (n = 8); 2) healthy elderly volunteers (n = 14); and 3) elderly patients with creatinine clearance between 30 and 70 ml/min (n = 13). Stereoselective gas chromatography-mass spectrometry was used to quantify deuterated S- and nondeuterated R- and S-ibuprofen in serum up to 24 hr after the first and last doses. Urinary excretion of the stereoisomeric forms of carboxyibuprofen, hydroxyibuprofen and ibuprofen glucuronide were determined up to 24-hr postdose by stereoselective high-performance liquid chromatography. Stereoselective serum protein binding was determined by ultrafiltration. Both elderly groups had significantly decreased binding of S-ibuprofen compared to the young group. The S-ibuprofen pharmacokinetics were significantly different in the elderly patients with renal impairment compared to the young volunteers: the T1/2 was increased, the unbound clearance was decreased and the unbound concentration at steady state was increased. Fraction inverted was similar for all groups, but unbound clearances of glucuronidation and hydroxylation were reduced in the elderly patients with renal impairment. These results suggest that the disposition of ibuprofen enantiomers is altered in elderly persons with renal impairment; these changes may increase the risk for nonsteroidal anti-inflammatory drug-associated adverse effects in such patients.

The pharmacokinetics of piroxicam in elderly persons with and without renal impairment.

1. Piroxicam pharmacokinetics were assessed in three groups of subjects: (1) young healthy volunteers, (2) healthy elderly subjects (mean +/- s.d. creatinine clearance 88 +/- 13 ml min-1), and (3) elderly patients with renal insufficiency (creatinine clearance 60 +/- 10 ml min-1) following the administration of piroxicam 20 mg as a single dose and after chronic dosing of 20 mg once daily for 4 weeks. 2. Piroxicam and 5'-hydroxypiroxicam concentrations were measured by h.p.l.c. in serum and urine samples collected for 96 h after the single dose and for 144 h after chronic dosing. Unbound concentrations of piroxicam were determined by ultrafiltration. 3. Elimination half-lives, steady state concentrations of piroxicam and 5'-hydroxypiroxicam, clearances of total and unbound piroxicam, volumes of distribution normalized for body weight, and urinary recovery of 5'-hydroxypiroxicam were not influenced by age or renal function. Volumes of distribution after the single dose were significantly lower in women compared with men (mean +/- s.d. 10.0 +/- 2.9 l vs 12.9 +/- 5.0 l; 95% confidence interval of the difference 0.1 to 5.6). 4. Percent unbound piroxicam values were 1.46 +/- 0.3% after the single dose and 1.45 +/- 0.2% at steady state. There were significant reductions in clearance and clearance of unbound piroxicam between single and chronic doses. The half-lives of 5'-hydroxypiroxicam (80.9 +/- 44 h) were significantly longer than those of piroxicam (54.9 +/- 26 h) after chronic dosing.

Lack of presystemic inversion of (R)- to (S)-ibuprofen in humans.

Presystemic inversion of (R)- to (S)-ibuprofen has been proposed but not directly examined in humans. We investigated the bioavailability of the enantiomers of ibuprofen in 10 healthy volunteers. Low-dose racemic ibuprofen (400 mg) was administered orally and intravenously (60-minute infusion), in random order. There were no significant differences between oral and intravenous doses for the area under the curve values, terminal rate constants, clearances, metabolite formation clearances, and serum protein binding for (R)- and (S)-ibuprofen. The bioavailabilities of (R)-ibuprofen and total ibuprofen were 0.92 +/- 0.11 and 0.95 +/- 0.08, respectively. The fractional inversion of (R)-ibuprofen was determined by two methods (stable isotope method and from the stereochemical composition of the urinary metabolites) that gave similar estimates of inversion for oral dosing (0.56 +/- 0.12 and 0.60 +/- 0.07, respectively) and intravenous dosing (0.56 +/- 0.09 and 0.60 +/- 0.06, respectively). We conclude that the bioavailability of both enantiomers of ibuprofen is complete and find no evidence of significant presystemic inversion.

Variability in the disposition of ibuprofen enantiomers in osteoarthritis patients.

The pharmacokinetics of the enantiomers of ibuprofen have been investigated following oral administration of 300 or 600 mg of racemic ibuprofen four times daily to 45 patients with osteoarthritis. Fifteen of these patients also received single doses of 300 or 600 mg of racemic ibuprofen. Serum concentrations of R- and S-ibuprofen and urine concentrations of the stereoisomers of ibuprofen and its metabolites were measured by high-performance liquid chromatography. The fraction inverted (F(inv)) of the inactive R- to active S-ibuprofen was estimated by a urinary metabolite method. For the 15 patients in both the chronic and single dose studies, there were no significant differences in the clearance of R-ibuprofen or F(inv). The elimination half-lives of R- and S-ibuprofen were comparable for the single and chronic dosing studies. The area under the curve (AUC) values, 6-h trough concentrations, and average steady state concentrations of the R- and S-enantiomers were statistically different after chronic dosing. Despite considerable variability in the clearances in these patients, e.g., clearance (CL) of R-ibuprofen showed 28-49% CV, much less variability was seen in F(inv) (range 9-19% CV), implying that patients would receive similar effective doses of active S-ibuprofen in spite of large differences in kinetics.

Correlation of serum concentrations of ibuprofen stereoisomers with clinical response in the treatment of hip and knee osteoarthritis.

Stereoselective pharmacokinetic measurements of the active enantiomer, S-ibuprofen, were correlated with clinical response in 45 participants in a randomized double blinded 4 week comparison of ibuprofen, 1200 or 2400 mg/day, for treatment of hip or knee osteoarthritis. Ibuprofen dose correlated with S-ibuprofen area under the serum concentration curve (AUC), trough and average concentration, but not with clinical outcome. AUC of S-ibuprofen correlated with improvement in disability, rest pain and in the physician's global assessment (p = 0.02, 0.08, and 0.10, respectively), and negatively with the subject's weight and creatinine clearance (p = 0.09 and 0.07, respectively). Some individual variation in responsiveness to ibuprofen (and other nonsteroidal antiinflammatory drugs) may be attributed to pharmacokinetic differences.

Stereoselective metabolism of ibuprofen in humans: administration of R-, S- and racemic ibuprofen.

Using stable isotope methodology, we studied the effect of the enantiomeric composition of dosage form on ibuprofen metabolism. Eight healthy human subjects received racemic ibuprofen (800 mg) plus S-[aromatic-2H4]ibuprofen (10 mg), R-ibuprofen (600 mg) plus S-[aromatic-2H4]ibuprofen (10 mg) and S-ibuprofen (600 mg) orally on separate occasions in random order. Stereoselective gas chromatography-mass spectrometry was used to quantify deuterated and nondeuterated ibuprofen in serum up to 24 h postdose. Urinary excretion of the stereoisomeric forms of carboxyibuprofen, hydroxyibuprofen and ibuprofen glucuronide were determined up to 24 h postdose by stereoselective high performance liquid chromatography. The metabolism of ibuprofen enantiomers was not influenced by the enantiomeric composition of the dose. For racemic ibuprofen, the mean clearances (+/- S.D.) of S-ibuprofen, R-ibuprofen inversion and R-ibuprofen noninversion were 87.4 +/- 25.9, 57.3 +/- 31.0 and 56.3 +/- 29.0 ml/min, respectively. The fractional inversion of ibuprofen was significantly greater (P less than .05) using the stereochemical composition of the urinary metabolites (0.63 +/- 0.05) vs. the method using the clearance of deuterated S-ibuprofen (0.51 +/- 0.08) after the dose of racemate. Unreliable estimates of fractional inversion were obtained when the S-ibuprofen and racemic ibuprofen doses were combined. Metabolite formation clearances suggested that S-ibuprofen is preferred over R-ibuprofen in the formation of hydroxyibuprofen, carboxyibuprofen and ibuprofen glucuronide. Product stereoselectivity in the formation of the four diastereomers of carboxyibuprofen was modest in favor of SS- and RR-carboxyibuprofen for S- and R-ibuprofen, respectively.

Binding of pyrimethamine to human plasma proteins and erythrocytes.

A high-performance liquid chromatographic (HPLC) assay was developed for pyrimethamine in plasma, red blood cells (RBCs), and buffer for the purpose of studying its plasma protein binding and RBC partitioning. Pyrimethamine (1000 ng/ml) was 94% bound to plasma proteins on average, depending on the pH of plasma. A comparison of the lower and upper range of plasma concentrations that would be achieved after a malaria prophylaxis dosing regimen (25 mg/week) showed that the fraction unbound was significantly lower at 120 ng/ml than at the upper plasma concentration of 360 ng/ml, 3.5 vs 4.9%, respectively. Nonlinear regression of the effect of albumin concentration (g/L) on plasma binding yielded the equation: fraction unbound = 1/[(0.421 * albumin concentration) + 1] (R2 = 0.99). There was no binding to normal levels of alpha 1-acid glycoprotein (AAG). The mean ratio of the concentration of pyrimethamine in RBCs to that in plasma (RBC:plasma ratio) was 0.42, while the mean RBC:buffer ratio was 5.2. Binding to hemolysate did not account for all of the RBC uptake, suggesting that binding to or partitioning into RBC membranes may be important. Because pyrimethamine binding depends on both albumin concentration and pyrimethamine concentration in the plasma, these studies predict greater free fractions of pyrimethamine associated with the higher doses given for toxoplasmosis (75 mg/day) and with the hypoalbuminemia associated with AIDS and malaria.

High-performance liquid chromatographic determination of the stereoisomeric metabolites of ibuprofen.

A stereospecific reversed-phase high-performance liquid chromatographic (HPLC) method has been developed to simultaneously quantitate the stereoisomers of the two major metabolites of ibuprofen: hydroxyibuprofen and carboxyibuprofen. The metabolites were derivatized with S-(alpha)-methylbenzylamine to form diastereomeric amides which were separated and quantified on a C8 column. The validity of the stereoselective assay was confirmed by comparison with a non-stereoselective HPLC method. The stereoselective assay was applied to the quantification of all the stereoisomeric ibuprofen metabolites in urine from human volunteers dosed with racemic ibuprofen or the individual enantiomers of ibuprofen. Significant substrate and product stereo-selectivities were observed in the formation of carboxyibuprofen.