In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelic variant forms of human liver microsomal cytochrome P450 2C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics.

In-vitro studies were conducted to assess the impact of CYP2C9 genotype on the metabolism (methyl hydroxylation) and pharmacokinetics of celecoxib, a novel cyclooxygenase-2 inhibitor and CYP2C9 substrate. When compared to cDNA-expressed wild-type CYP2C9 (CYP2C9*1), the Vmax/Km ratio for celecoxib methyl hydroxylation was reduced by 34% and 90% in the presence of recombinant CYP2C9*2 and CYP2C9*3, respectively. These data indicated that the amino acid substitution at position 359 (Ile to Leu) elicited a more pronounced effect on the metabolism of celecoxib than did a substitution at position 144 (Arg to Cys). The Vmax/Km ratio was also decreased in microsomes of livers genotyped CYP2C9*1/*2 (47% decrease, mean of two livers), or CYP2C9*1/*3 (59% decrease, one liver). In all cases, these changes were largely reflective of a decrease in Vmax, with a minimal change in Km. Based on simulations of the in-vitro data obtained with the recombinant CYP2C9 proteins, it was anticipated that the pharmacokinetics of celecoxib (as a much as a five-fold increase in plasma AUC) would be altered (versus CYP2C9*1/*1 subjects) in subjects genotyped heterozygous or homozygous for the CYP2C9*2 (Cys144) or CYP2C9*3 (Leu359) allele. In a subsequent clinical study, the AUC of celecoxib was increased (versus CYP2C9*1/*1 subjects) approximately 2.2-fold (range, 1.6-3-fold) in two CYP2C9*1/*3 subjects and one CYP2C9*3/*3 subject receiving a single oral dose (200 mg) of the drug. In contrast, there was no significant change in celecoxib AUC in two subjects genotyped CYP2C9*1/*2.

Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers.

Steady-state inhibitory activity of rofecoxib (Vioxx) on COX-2 versus COX-1 was compared with that of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) in 76 healthy volunteers randomized to placebo, rofecoxib 12.5 mg qd, rofecoxib 25 mg qd, diclofenac 50 mg tid, ibuprofen 800 mg tid, sodium naproxen 550 mg bid, or meloxicam 15 mg qd. All of these doses include the high end of the approved clinical dose range. Ex vivo whole-blood assays were used to determine the effect on COX-2 and COX-1 activity, respectively. Urinary prostanoids were also measured. Mean inhibition of COX-2 (measured as the weighted average inhibition [WAI] of lipopolysaccharide [LPS]-induced PGE2 generation over 8 hours on day 6 vs. baseline) was -2.4%, 66.7%, 69.2%, 77.5%, 93.9%, 71.4%, and 71.5% for placebo, rofecoxib 12.5 mg, rofecoxib 25 mg, meloxicam, diclofenac, ibuprofen, and naproxen, respectively. Corresponding values for mean inhibition of COX-1 (measured as TXB2 generation in clotting whole blood) were -5.15%, 7.98%, 6.65%, 53.3%, 49.5%, 88.7%, and 94.9%. Rofecoxib had no significant effect on urinary excretion of 11-dehydro TXB2, a COX-1-derived product. These data support the contention that rofecoxib is the only drug of the regimens tested that uniquely inhibits COX-2 without affecting COX-1.

Pharmacokinetics, COX-2 specificity, and tolerability of supratherapeutic doses of rofecoxib in humans.

OBJECTIVE: Prostaglandin synthesis is catalyzed by a constitutive cyclo-oxygenase isoform (COX-1) and an inducible isoform (COX-2). It is hypothesized that the analgesic and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (nonspecific COX-1/COX-2 inhibitors) such as ibuprofen principally derive from COX-2 inhibition. The purpose of this study was to evaluate steady-state pharmacokinetics, biochemical selectivity and tolerability of rofecoxib (Vioxx), characterized in vitro as a COX-2 inhibitor. METHODS: Four panels of healthy men (n = 8 per panel) were administered rofecoxib (n = 6) (25, 100, 250, 375 mg) or placebo (n = 2) once daily on day 1 and days 3-14. Blood samples for assays of rofecoxib plasma concentration and COX isoform activity were obtained pre-dose and at specified time points post-dose. RESULTS: Rofecoxib pharmacokinetics were found to be complex and nonlinear. Elimination half-life ranged from 9.9 h to 17.5 h after multiple dosing with an accumulation ratio close to 2 for all doses. COX-2 inhibitory activity as assessed by average inhibition of whole blood lipopolysaccharide-stimulated prostaglandin E2 over the 8-h post-dose period on day 14 was 0.3, 67, 96, 92 and 96% for the placebo and the 25-, 100-, 250- and 375-mg treatment groups, respectively. No treatment group showed significant inhibition of COX-1 as assessed by thromboxane B2 generation in clotting whole blood. Side effects were mild and transient. CONCLUSION: The results indicate that rofecoxib is a potent and specific inhibitor of COX-2 in humans even at doses more than tenfold higher than those associated with efficacy in patients with osteoarthritis.

Effect of multiple doses of montelukast, a CysLT1 receptor antagonist, on digoxin pharmacokinetics in healthy volunteers.

The effect of multiple oral doses of montelukast, a cysLT1 receptor antagonist, on the pharmacokinetics of oral digoxin was studied in healthy male volunteers in a randomized double-blind two-period crossover study. Subjects received 10 mg of montelukast or placebo daily for 11 days. On day 7, they received a single 0.5 mg oral dose of digoxin elixir. The pharmacokinetic parameters of digoxin (AUC0-->24' AUC0-->infinity' Cmax' tmax' t1/2) and cumulative urinary excretion over 120 hours were not affected by the multiple doses of montelukast. The 90% confidence interval for each of these parameters fell within prespecified clinically acceptable bounds. Side effects were mild and transient. This suggests that concurrent administration of montelukast and digoxin was well tolerated. Concurrent treatment with montelukast has no effect on the pharmacokinetics of digoxin.

Effect of montelukast on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers.

Montelukast, a cysteinyl leukotriene receptor antagonist, is being developed for the treatment of asthma and related diseases. This study was designed to evaluate whether montelukast at clinically used dosage levels would interfere with the anticoagulant effect of warfarin. In a two-period, double-blind, randomized crossover study, 12 healthy male subjects received a single oral dose of 30 mg warfarin on the 7th day of a 12-day treatment with montelukast, 10 mg daily by mouth, or a placebo. Montelukast had no significant effect on the area under the plasma concentration-time curves and peak plasma concentrations of either R- or S-warfarin. However, slight but statistically significant decreases in time to peak concentration of both warfarin enantiomers and in elimination half-life of the less potent R-warfarin were observed in the presence of montelukast. These changes were not considered as clinically relevant. Montelukast had no significant effect on the anticoagulant effect of warfarin, as assessed by the international normalized ratio (INR) for prothrombin time (AUC0-144 and INR maximum). The results of this study suggest that a clinically important interaction between these drugs is unlikely to occur in patients requiring concomitant administration of both drugs.

Pharmacokinetic and pharmacodynamic interaction between the lipoxygenase inhibitor MK-0591 and the cyclooxygenase inhibitor ibuprofen in man.

Twelve healthy male subjects participated in a double-blind, placebo-controlled, randomized, three-period, crossover study to investigate the safety, tolerability, biochemical activity and pharmacokinetics of ibuprofen, a cyclooxygenase inhibitor and MK-0591, a 5-lipoxygenase inhibitor, given as single entities and in combination. Each subject received for three consecutive 8-day periods, separated by 1 week washout, each of the following treatments: ibuprofen 600 mg three times a day with 125 mg MK-0591 twice a day, ibuprofen 600 mg three times a day with placebo for MK-0591 and MK-0591 125 mg twice a day with placebo for ibuprofen. Cyclooxygenase inhibition was measured by platelet thromboxane (TxB2) generation test, and 5-lipoxygenase inhibition was measured by urinary leukotriene E4 excretion and ex vivo LTB4 generation in calcium-ionophore-stimulated blood. TxB2 suppression on day 8 by ibuprofen was not affected by concomitant treatment with MK-0591. MK-0591 alone had no effect on TxB2 generation. Leukotriene biosynthesis was inhibited by more than 90% by MK-0591 alone and by combined treatment, while ibuprofen alone had no effect. Coadministration appears to affect the pharmacokinetics of MK-0591 (decrease of area under the plasma concentration-vs-time curve [AUC] and maximum plasma concentrations [Cmax]) and of ibuprofen (increase of AUC and half-lives of elimination (t1/2) of the (S)-enantiomer, increase of t1/2 the (R)-enantiomer). Combined treatment had no effect on creatinine clearance nor on the number and intensity of the reported adverse experiences.

Effect of clopidogrel on naproxen-induced gastrointestinal blood loss in healthy volunteers.

The effect of clopidogrel, a potent inhibitor of platelet aggregation, on naproxen-induced faecal blood loss was investigated in 30 healthy volunteers in a randomized, double-blind, placebo-controlled, two parallel treatment groups study. All subjects first received naproxen 250 mg b.i.d. during 7 days, after which they were randomly allocated to additionally receive either clopidogrel 75 mg once daily (n = 15) or matching placebo (n = 15) for 11 days. Faecal blood loss was measured by the 51Cr-labelled erythrocyte method during the last four days of each of the four study periods, i.e. baseline, treatment with naproxen alone, combined treatment and wash-out. Mean daily faecal blood loss was below 0.5 ml/day during the baseline period in both treatment groups and increased during treatment with naproxen alone to (mean +/- SD) 1.14 +/- 0.58 ml/day in the naproxen + placebo group and to 1.93 +/- 1.51 ml/day in the naproxen + clopidogrel group. Addition of clopidogrel to naproxen treatment was associated with an increase of the mean daily blood loss to 6.83 +/- 9.32 ml/day, which was statistically significantly higher than 1.75 +/- 1.40 ml/day observed during treatment with naproxen + placebo. During the wash-out period, mean daily blood loss decreased to 0.98 +/- 0.51 ml/day in the naproxen + placebo group and to 1.07 +/- 0.46 ml/day in the naproxen + clopidogrel group. Based on these results, it can be concluded that clopidogrel increases naproxen-induced gastrointestinal blood loss in healthy volunteers. Caution should therefore be called for when these drugs are coadministered.

Effect of MK-386, a novel inhibitor of type 1 5 alpha-reductase, alone and in combination with finasteride, on serum dihydrotestosterone concentrations in men.

Two isozymes (types 1 and 2) of 5 alpha-reductase (5 alpha R; EC 1.3.99.5), with differential tissue distribution, have been identified in humans. These enzymes catalyze the reduction of testosterone (T) to dihydrotestosterone (DHT). The contributions of each of these isozymes to serum and tissue concentrations of DHT remain to be fully defined. Finasteride, a selective inhibitor of type 2 5 alpha R, lowers circulating DHT levels by approximately 70% in men after treatment with 5 mg daily. MK-386 (4,7 beta-dimethyl-4-aza-5 alpha-cholestan-3-one) is a new selective inhibitor of type 1 5 alpha R. A single rising dose, alternating panel, trial in 16 healthy males (age range, 21-25 yr) studied the effect of 0.1-100 mg MK-386. DHT was maximally reduced by 20-30% relative to placebo at MK-386 doses of 10 mg or more, orally, by 24 h posttreatment (P < 0.01 vs. placebo). No consistent effect on T concentrations was evident. In a second trial, finasteride (5 mg) was given for 19 days to 10 healthy young men (age range, 24-47 yr); a 25-mg dose of MK-386 was added for 2 days of combination therapy after at least 10 days of finasteride treatment. Withdrawal of MK-386 was followed by 5-6 days of finasteride follow-up treatment. Finasteride alone reduced DHT, on the average, by 68.7% (SE = 3.4%). Addition of MK-386 suppressed DHT by 89.5% (SE = 1.4%) relative to baseline (P < 0.01 vs. effect of finasteride alone). Small increases in serum T were observed with finasteride alone and in combination with MK-386 (approximately 10% and 19%, respectively). These data are consistent with selective 5 alpha R type 1 inhibition in man by MK-386 and the prediction that types 1 and 2 5 alpha R account for all, or nearly all, of circulating DHT. Further clinical trials are needed to assess the therapeutic utility of type 1 5 alpha R inhibition as well as that of combined inhibition of types 1 and 2 5 alpha R.

Liquid chromatographic determination of total celiprolol or (S)-celiprolol and (R)-celiprolol simultaneously in human plasma.

A method has been developed for the determination of total celiprolol (sum of enantiomers) or the enantiomers (R)-celiprolol and (S)-celiprolol in plasma by high-performance liquid chromatography with UV and fluorescence detection. After extraction from alkalinized plasma with methyl-tert.-butyl ether and back-extraction into 0.01 M HCl (for total celiprolol determination) or after evaporation of the organic phase and derivatisation with R(-)-1-(1-naphthyl)ethyl isocyanate (enantiomer determination), total celiprolol or its diastereomeric derivatives were chromatographed on a reversed-phase HPLC column with a mixture of acetonitrile and phosphate buffer pH 3.5 (+0.05% triethylamine). Acebutolol was used as internal standard. Linearity was obtained in the range of 5 to 2000 ng/ml for total and 2.5 to 500 ng/ml for enantiomer determination. Intra-day and inter-day variation was lower than 10%. The method can be applied for analysis of plasma samples obtained from patients treated with oral racemic celiprolol doses.

Lack of a pharmacokinetic interaction between moexipril and hydrochlorothiazide.

OBJECTIVE: To investigate the potential for pharmacokinetic interactions between moexipril, a new converting enzyme inhibitor, and hydrochlorothiazide after single dose administration. METHODS: 12 healthy male volunteers were studied by an open, randomised, three-way cross-over design, in which single doses of moexipril, hydrochlorothiazide and the two drugs together were administered. Blood and urine were collected up to 48 hours for measurement of the concentrations of moexipril and its metabolite moexiprilat. In addition, the urine samples were analysed for hydrochlorothiazide. RESULTS: For the area under the plasma concentration-time curve calculated from time 0 to a concentration greater than zero, AUC(O-t), the study showed a mean value of moexipril 437 ng.ml-1.h-1 following administration of moexipril alone and 416 ng.ml-1.h-1 following moexipril concomitantly with hydrochlorothiazide. The corresponding values for the metabolite moexiprilat were 203 and 215 ng.ml-1.h-1, respectively. The Cmax of moexipril and the metabolite (data of the metabolite in parenthesis) were 245.4 (70.8) ng.ml-1 after administration of moexipril alone and 241.0 (69.2) ng.ml-1 after coadministration of hydrochlorothiazide. The mean total renal excretion (TUE) of hydrochlorothiazide was 15.2 mg when administered alone and 15.1 mg when given together with moexipril. The corresponding mean TUE-values for moexiprilat were 334 (1200) and 453 (1460) micrograms. CONCLUSIONS: The coadministration of moexipril with hydrochlorothiazide had no demonstrable effect on the measured pharmacokinetic parameters of moexipril, its active metabolite moexiprilat or hydrochlorothiazide.

Biochemical activity, pharmacokinetics and tolerability of tepoxalin, a cyclooxygenase/5-lipoxygenase inhibitor, in man.

Tepoxalin, a novel inhibitor of cyclooxygenase (CO) and 5-lipoxygenase (5-LO), was investigated for biochemical activity and pharmacokinetics in two studies. Study I was a 4-period, double-blind, randomized, single rising dose using 2 alternating panels (A, B) with interspersed placebo design (A: 25, 100, 400 mg, B: 50, 200, 800 mg p.o.). Study II was a 3-panel, randomized, placebo-controlled, double-blind, multiple dose study (A: 100 mg, B: 200 mg, C: 400 mg). In both studies, CO inhibition was assessed by generation of serum thromboxane (TxB2), 5-LO activity by LTB4 production ex vivo in Caionophore-stimulated blood. Plasma drug concentrations were assayed by HPLC for tepoxalin and its identified acid metabolite. It was found in both studies that at all dose levels the TxB2 generation was markedly suppressed (> 95% 2 h postdose). In study I, at 2 h postdose, % inhibition of LTB4 biosynthesis was marginal for the 3 lower doses but significant at 200 (14%), 400 (25%) and 800 mg (43%). In study II, the only significant inhibition occurred at the 400 mg dose at 6 h postdose on day 1 (17%) and on day 8 at 4, 6 and 8 h postdose (32, 42 and 32% respectively). In both studies and at all doses, plasma concentrations of tepoxalin varied widely between subjects. Linearity between plasma concentrations and dose could not be ascertained, and correlation between drug plasma levels and effect on LTB4 synthesis was poor. Single doses up to 800 mg and multiple doses up to 400 mg of tepoxalin were generally well tolerated.

Pharmacokinetics and pharmacodynamics of multiple oral doses of MK-0591, a 5-lipoxygenase-activating protein inhibitor.

The pharmacodynamics, kinetics, and tolerability of a new orally active 5-lipoxygenase inhibitor were evaluated in healthy male volunteers. MK-0591, 50, 125, and 250 mg every morning and 250 mg every 12 hours, was administered for 10 days. Leukotriene B4 biosynthesis ex vivo in ionophore (A23187)-stimulated whole blood and leukotriene E4 levels in urine were determined. Leukotriene B4 production was inhibited up to 90% of baseline for 12 hours after administration at the highest dose. The degree of leukotriene B4 inhibition ex vivo in whole blood significantly correlated with plasma MK-0591 concentrations (0 to 1500 ng/ml; r = 0.73). Urinary leukotriene E4 was inhibited by > 80% at 24 hours after administration for all dose levels. Pharmacokinetics of MK-0591 were linear, with a half-life of approximately 6 hours. Very little accumulation was seen after multiple dosing. MK-0591 had no effect on testosterone levels, and good tolerability was shown at all dose levels of MK-0591 administered for up to 10 days.

Plasma concentrations and effect on testosterone metabolism after single doses of MK-0434, a steroid 5 alpha-reductase inhibitor, in healthy subjects.

A four-period, two-panel, single-rising-dose study (0.1-100 mg) was conducted in healthy males to investigate the pharmacodynamics, tolerability and pharmacokinetics of MK-0434, a steroid 5 alpha-reductase inhibitor. MK-0434 was associated with a significant reduction in dihydrotestosterone, which was maximal at 24 h and maintained through 48 h post treatment. The maximum reduction was approximately 50% and occurred at all doses above 5 mg (10, 25, 50 and 100 mg). MK-0434 appeared to have no effect on serum testosterone at these single doses. Rising single doses of MK-0434 were associated with an increase in Cmax and AUC but the changes were less than proportional to dose, most likely due to nonlinear absorption. MK-0434 given in single doses up to 100 mg was without significant adverse effects in healthy male volunteers. In summary, MK-0434 is a well-tolerated, potent, orally active 5 alpha-reductase inhibitor in man.

Human pharmacokinetics and tolerability of L-697,639, a non-nucleoside HIV-1 reverse transcriptase inhibitor.

L-697,639, a potent and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase and HIV-1 replication in vitro, was administered to healthy male volunteers to investigate the pharmacokinetics and tolerability of single and multiple oral doses. Single doses ranging from 25 to 500 mg, and multiple doses of up to 100 mg every 12 h for ten days, produced no clinically important adverse events. Dose proportionality with respect to AUC was seen over the range of 25-100 mg administered as a single dose. Single doses of 200 mg and 500 mg resulted in an increase in AUC and Cmax that was less than proportional to the increase in dose. The mean Cmax after single doses of 25 and 500 mg were 0.9 and 5.8 microM respectively. Mean Tmax values ranged from 1.7-3 h. Mean AUCs (0-48 h) were from 6.05 to 50.3 microM h after doses from 25 to 500 mg respectively. After the 500-mg dose less than 0.7% appeared unchanged in the urine over 48 hours. During multiple doses, steady-state was reached on day 3 and slight accumulation occurred (approximately 1.5-fold). L-697,639 was well tolerated for up to ten days at doses that resulted in mean steady-state trough concentrations that exceed their in-vitro susceptibilities.

Moexipril does not alter the pharmacokinetics or pharmacodynamics of warfarin.

The potential effect of moexipril, a new converting enzyme inhibitor, on the pharmacokinetics and pharmacodynamics of a single dose of warfarin has been investigated. Ten healthy male volunteers received in a randomised crossover fashion a single oral dose of 50 mg warfarin sodium alone and together with the first dose of 6 days of oral treatment with moexipril 15 mg o.d. Mean oral plasma clearance of (R)-warfarin was 175 ml.h-1 in the absence and 181 ml.h-1 in the presence of moexipril, and the corresponding values for (S)-warfarin were 248 ml.h-1 and 249 ml.h-1. Apparent volume of distribution, peak plasma concentration, time to reach peak concentration and area under the plasma concentration-time curve both of (R)- and (S)-warfarin were not significantly affected. Moexipril did not alter the maximum prothrombin time (20.3 versus 20.1 s, respectively in the absence and presence of moexipril), time to maximum response (48.0 versus 50 h) and area under the prothrombin time versus time curve. The results suggest that a clinically important interaction between moexipril and warfarin is unlikely to occur in patients treated with both drugs.

Pharmacodynamics and tolerability of L-654,066, a steroid 5 alpha-reductase inhibitor, in men.

A four-period, two-panel single rising-dose study (0.1 to 100 mg) was conducted in healthy men to investigate the pharmacodynamics and tolerability of L-654,066, a steroid 5 alpha-reductase inhibitor. Within each panel, six subjects received L-654,066 and two subjects received placebo at each dose level; the placebo subjects changed between periods so that each subject received placebo once. Testosterone and dihydrotestosterone were measured in serum at 0, 4, 24, and 48 hours after each treatment. L-654,066 was associated with a significant reduction in serum dihydrotestosterone concentrations, which was maximal at 48 hours after dose. Forty-eight hours after treatment, mean percentage of inhibition was 24% and 39% for the 0.1 and 0.5 mg doses, respectively, and ranged from 50% to 65% at doses from 1 to 25 mg and from 70% to 75% at doses from 50 to 100 mg. Testosterone serum levels did not show any significant difference between the various treatments, including placebo.

Lack of effect of flunarizine on the pharmacokinetics and pharmacodynamics of sumatriptan in healthy volunteers.

Twenty-four healthy subjects completed a double-blind, placebo controlled, parallel group study to evaluate the effect of treatment with flunarizine on the pharmacokinetics and pharmacodynamics of sumatriptan, a 5HT1-like agonist. Subjects received a single oral 200 mg dose of sumatriptan on the eighth day of a once daily treatment with either flunarizine 10 mg or matching placebo. There were no significant differences between treatments in relation to Cmax (82.3 ng ml-1 in the absence and 81.4 ng ml-1 in the presence of flunarizine), AUC (368 ng ml-1 h in the absence and 360 ng ml-1 in the presence) and elimination half-life (2.2 h in the absence and 2.4 h in the presence of flunarizine) of sumatriptan. Similarly pretreatment with flunarizine was not found to have any clinically significant effect on the pharmacodynamics of sumatriptan as measured by pulse rate, blood pressure and ECG.

Tolerance and pharmacokinetics of propacetamol, a paracetamol formulation for intravenous use.

In 12 healthy volunteers, paracetamol pharmacokinetics were compared following administration of 1 g propacetamol HCl given intravenously over a 15-min period and 500 mg paracetamol given orally. Mean +/- SD total AUC (microgram/ml.h) following the iv formulation was significantly (P < 0.01) greater than following oral paracetamol (25.53 +/- 4.27 vs 21.04 +/- 4.49) corresponding to a mean oral bioavailability of paracetamol of 82.2 +/- 9.4%. Between 1 and 2 h after administration, paracetamol plasma concentrations became very similar following both formulations. In another study, 2 g propacetamol HCl was given both as a 15-min infusion and as a 2-min bolus injection to six healthy volunteers. Contrary to mild to moderate local discomfort experienced during the 2-min bolus injection, the 15-min infusion was well tolerated without any complaints reported.

Plasma drug profiles and tolerability of MK-571 (L-660,711), a leukotriene D4 receptor antagonist, in man.

We have studied the tolerability and plasma drug profiles of a leukotriene D4 receptor antagonist, MK-571, given intravenously and as an oral solution in two separate trials. Study I (i.v.) involved 2 panels of 6 healthy men in a double-blind, alternating, incrementally increasing dose study with single doses up to 1500 mg. There was good tolerability at all doses. Plasma was assayed stereospecifically by HPLC for the S(+) and R(-) enantiomers of MK-571. For each enantiomer AUC values increased more than proportionately with increasing dose, suggesting nonlinear kinetics. The S(+) enantiomer was cleared more rapidly than the R(-) enantiomer. The apparent initial volume of distribution was less than 101 for both enantiomers. Study II (oral) involved 18 healthy subjects in 3 parallel groups who took multiple oral doses of 100, 300, and 600 mg t.i.d. for 31 doses. MK-571 administration was well tolerated, with only mild to moderate gastrointestinal discomfort at the highest dose. Total MK-571 (plasma samples assayed nonstereoselectively) was rapidly absorbed after oral administration, reaching peak concentrations at 1-2 h. Mean 8 h AUC increased from dose 1 to dose 31 in all subjects at all doses, suggesting a modest extent of accumulation (about 50%) of total MK-571 in plasma with a t.i.d. dosage regimen.

Dose-dependent kinetics of the enantiomers of MK-571, and LTD4-receptor antagonist.

The disposition of the enantiomers of MK-571 (MK-0679 and L-668,018) following single i.v. doses of MK-571 (L-660,711) was studied in a three way cross-over study in 12 healthy male volunteers. Each volunteer received 75 mg, 300 mg and 600 mg i.v. doses of MK-571 at weekly intervals. The disposition of both enantiomers appeared dose-dependent, since the AUC increased disproportionately faster than the dose. The dose dependency was much more pronounced for L-668,018: its AUC increased 6-fold from the 75 to the 300 mg dose, 16-fold from 75 to 600 mg and 2.7 fold from 300 to 600 mg. For MK-0679, the corresponding increases in AUC were 4.8-, 11-, and 2.3 fold. Regardless of dose, the elimination of L-668,018 was more rapid than that of MK-0679. The disposition of MK-0679 needs to be investigated independently to detect any potential influence of L-668,018 on its disposition.