Stereoselective pharmacokinetics of flurbiprofen in humans and rats

Flurbiprofen, a 2-arylpropionic acid (2-APA) nonsteroidal anti-inflammatory drug (NSAID), exists as racemate and is used as such. Although the activity of 2-APAs is due mainly to their S-enantiomers, information on the pharmacokinetics of flurbiprofen is usually based on the measurement of total concentrations of S- and R-flurbiprofen. In this work, the pharmacokinetics of flurbiprofen enantiomers following single doses were studied in humans and rats. Upon iv administration of 10 mg/kg of racemic flurbiprofen to male Sprague-Dawley rats, the plasma concentrations were consistently higher for S-flurbiprofen than for R-flurbiprofen (AUC = 134 +/- 39 versus 41 +/- 9 mg.L-1 h). In bile duct-cannulated rats, the biliary excretion contained only 3.6-5.2% of the dose as conjugated flurbiprofen (S:R = 1.2-2.1). After administration of R-flurbiprofen to the rat, both enantiomers were found in plasma [AUC(R):AUC(S) = 0.10-0.16], indicating a limited extent of enantiomeric bioinversion. This is consistent with the previously reported limited extent of flurbiprofen uptake into fat. In healthy volunteers also, significant stereoselectivity was observed in the plasma concentration of the drug after 100-mg oral racemic doses [AUC-(S):AUC(R) = 45.4 +/- 12.7:40.1 +/- 14.3 mg.L-1.h]. As compared with the R-enantiomer, S-flurbiprofen has a smaller volume of distribution (7.23 +/- 1.9 versus 8.41 +/- 3.0 L) and total clearance (1.23 +/- 0.34 versus 1.47 +/- 0.50 L/h), but an equal half-life (4.21 +/- 1.2 versus 4.18 +/- 1.3 h). In urine, on the other hand, the R-configuration was predominant, as greater amounts of the R-enantiomer were found both as conjugated flurbiprofen and as an unidentified metabolite. Negligible amounts of intact flurbiprofen enantiomers were detected in urine. The observed stereoselectivity in humans cannot be attributed to enantiomeric bioinversion, as S-flurbiprofen was not detected in plasma and urine after oral administration of R-flurbiprofen.     

Disease-drug interaction: Reduced response to propranolol despite increased concentration in the rat with inflammation

Inflammatory conditions reduce clearance, hence increase plasma concentration of drugs such as propranolol that are efficiently cleared by the liver. The therapeutic consequences of this increased plasma drug concentration is mainly unknown. However, for sotalol, another beta-adrenergic antagonist, inflammation causes reduced potency. Sotalol, however, is renally cleared; hence, its clearance is unaffected by inflammation. We examined if the inflammation-induced increased plasma propranolol concentration compensates for the reduced responsiveness. A modified lead I ECG was used to record PR interval and heart rate (HR). ECG was monitored following oral administration of 3, 5, 10, 15, 20, 25, and 30 mg/kg propranolol to both control and adjuvant arthritis (AA) rats. To confirm altered pharmacokinetics, single 25 mg/kg doses of propranolol were administered to both AA and control rats, with an inserted cannula in their right jugular vein for serial blood sampling. As expected, AA caused a significant reduction in the propranolol oral clearance and subsequently substantial increases in plasma total and unbound drug concentration. Interestingly, however, despite the elevated propranolol concentrations, the effect on HR remained unchanged and the prolongation of PR interval was significantly reduced in AA compared with control rats. The reduced sensitivity to propranolol in AA rats is suggestive of altered beta-adrenergic receptors function.     

Comparison of the Pharmacokinetics and Pharmacodynamics of the Aldose Reductase Inhibitors,AL03152 (RS), AL03802 (R), and AL03803 (S)

The pharmacokinetics of AL03152 (RS) and its enantiomers, AL03802 (R) and AL03803 (S), were studied in the Sprague–Dawley rat following intravenous bolus administration. The enantiomers had differing pharmacokinetic profiles, while the racemic compound exhibited pharmacokinetic parameters approximating the mean values of the individual enantiomers. The total clearance (CL_T) values of the two enantiomers were similar, but the intrinsic clearance (Cl_int) was much greater for the S-enantiomer than for the R-enantiomer. The volume of distribution (V_ss) for AL03802 (R) was threefold greater than that for AL03803 (S). The stereoselectivity in V _ss could not be totally accounted for by the slight difference in serum protein binding of the isomers and resulted in a difference in the half-lives of the enantiomers. Only the R-isomer exhibited a persistent terminal elimination phase, consistent with more extensive tissue binding than the S-isomer. AL03152 enantiomers were equivalent in potency assessed from in vitro IC₅₀ values toward rat lens aldose reductase and rat kidney L-hexonate dehydrogenase and lens EC₅₀ values in diabetic rats.     

Comparison of the rat liver microsomal metabolism of the enantiomers of warfarin and 4′-nitrowarfarin (Acenocoumarol)

1. Rat liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol (4′-nitrowarfarin) has been studied. The enantiomers of both compounds were hydroxylated mainly at the 6- and 7-positions. Acenocoumarol enantiomers were much better substrates for cytochromes P-450 than the corresponding warfarin enantiomers; K_m values for the 6- and 7-hydroxylations were 2 to 19 times lower for R- and S-acenocoumarol than for warfarin.

2. Formation of the 6-, 7-, and 8-hydroxy-metabolites of warfarin was stereoselective for the R-enantiomer (the R/S ratio for total intrinsic clearance was about 3). 4′-Hydroxylation was not stereoselective. In contrast, formation of acenocoumarol metabolites was stereoselective for the S-enantiomer (the S/R ratio for total intrinsic clearance was about 3).

3. From the effects of phenobarbitone and methylcholanthrene induction, and inhibition by cimetidine, on in vitro metabolism of the enantiomers of both compounds, it was concluded that the differences between warfarin and acenocoumarol can be explained partly by the involvement of different enzymes.     

Effect of adjuvant arthritis on the disposition of acebutolol enantiomers in rats.

Disease states such as arthritis may interact with the kinetics of beta-blockers. Acebutolol (AC) is a chiral beta-blocker which is available as a racemate. The beneficial properties of AC, however, is attributed mainly to the S-(+)-enantiomer. The disposition of AC enantiomers and their active, chiral metabolites, diacetolol (DC) were examined after oral administration to healthy and adjuvant-induced arthritic (AA) female Sprague-Dawley rats. Arthritis was induced by tail base injection of Mycobacterium butyricum. Swelling of hind and forepaws were apparent in 10-16 days in AA but not controls. Control and AA rats were sacrificed at 0.5, 1, 2, 4, 6 and 8 h after a 25 mg/kg oral AC dose and blood was collected (n = 6). Significant three to tenfold increases in the initial plasma concentrations (0.5-2 h) of AC were observed in AA. Enantiomers were equally affected, thus AC S:R ratio was not changed. Higher plasma concentrations of the metabolite were only significant at 2 h. The ratio of DC:AC, however, was unaffected by AA. The DC S:R ratio was significantly decreased at 0.5 and 1 h in AA. The limited protein binding of AC (10%) was neither stereoselective nor affected by AA. Reduced intrinsic clearance in AA may be responsible for these observations.     

Polymorphic flecainide disposition under conditions of uncontrolled urine flow and pH

Summary The pharmacokinetics of R- and S-flecainide have been determined in five poor (PM) and five extensive (EM) metabolisers of sparteine/debrisoquine under conditions of uncontrolled urine flow and pH. The half-lives of R- and S-flecainide in PMs (R 19.3 h; S 16.1 h) were approximately twice those observed in EMs (R 8.8 h; S 9.1 h). The apparent oral clearances of R- and S-flecainide were lower in PMs (R 313 ml·min^–1; S 379 ml·min^–1) than in EMs (R 783 ml·min^–1; S 828 ml·min^–1). The renal clearance, however, was comparable for both enantiomers in both EMs and PMs, and therefore the phenotypic differences in flecainide disposition observed must be due to differences in metabolic clearance. The nonrenal clearance of both enantiomers was significantly lower in poor (R 123 ml·min^–1; S 201 ml·min^–1) relative to extensive metabolisers (R 533 ml·min^–1; S 586 ml·min^–1). The partial clearance to the two major metabolites meta-O-dealkylated flecainide (MODF) and the meta-O-dealkylated lactam of flecainide (MODLF) was significantly lower in poor (62 ml·min^–1) than extensive (267 ml·min^–1) metabolisers.The impairment in flecainide metabolism in poor metabolisers of sparteine/debrisoquine has therefore been confirmed. Under conditions reflecting the clinical situation the difference in disposition between EMs and PMs would be considerable. However, it may be predicted that at standard doses concentrations greater than 1000 ng·ml^–1 would not be attained in the PMs studied. The serum protein binding of R- and S-flecainide was studied in each subject and no differences between the enantiomers or the phenotypes were observed (Free fraction EM: R 0.43; S 0.42; PM R: 0.46; S: 0.46). Enantioselective disposition was noted in all PMs studied, due to a significantly lower nonrenal clearance of the R-enantiomer. In extensive metaboliser subjects, considerable interindividual variation in the enantioselective disposition of flecainide was noted, ranging from metabolism favouring either enantiomer to the absence of any selectivity.Presented in part at the 23rd Annual Meeting of the Australasian Society of Clinical and Experimental Pharmacologists, Sydney, 4–6 December, 1989     

Effect of Experimental Diabetes Mellitus and Arthritis on the Pharmacokinetics of Hydroxychloroquine Enantiomers in Rats

Purpose. To study the effect of experimental diabetes and arthritis on the pharmacokinetics of hydroxychloroquine (HCQ) enantiomers in rats. Methods. The pharmacokinetic studies were carried out following administration of 40 mg/kg of racemic HCQ to diabetic, insulin-treated diabetic, adjuvant arthritic and control rats. Results. Renal (70% and 62% for R- and S-HCQ, respectively) and non-renal clearance (100% and 145% for R- and S-HCQ, respectively) of HCQ enantiomers were significantly increased in diabetic rats. Diabetes-induced alterations in the disposition of HCQ were reversed by insulin treatment. In arthritic rats, systemic clearance (CL) of HCQ enantiomers was significantly reduced (1.05 ± 0.15 and 1.3 ± 0.19 1/h/kg for R- and S-HCQ, respectively) compared to controls (1.69 ± 0.32 and 1.93 ± 0.34 1/h/kg for R- and S-HCQ, respectively). The fraction unbound of the R- and S-HCQ were 49.4% and 50.5% lower in platelet rich plasma of arthritic rats compared to healthy rats. Increased blood concentrations of HCQ enantiomers in arthritic rats were significantly related to the degree of inflammation. Conclusions. Diabetes significantly increased the CL of both R- and S-HCQ by increasing renal and non-renal clearance. Arthritis caused a significant decrease in CL of HCQ enantiomers through increased binding and a decreased intrinsic clearance. The effect of the diseases on the pharmacokinetics of HCQ, however, was not stereoselective.This work was presented, in part, at the Ninth Annual Meeting of the American Association of Pharmaceutical Scientists,     

Drug-disease interactions: reduced beta-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 beta-adrenergic receptor and potassium channel antagonist. Racemic sotalol (40 mg kg(-1)) was administered to healthy, acutely (interferonalpha 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 (beta-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 (beta-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 beta-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.     

Comparison of the rat liver microsomal metabolism of the enantiomers of warfarin and 4'-nitrowarfarin (acenocoumarol)

1. Rat liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol (4'-nitrowarfarin) has been studied. The enantiomers of both compounds were hydroxylated mainly at the 6- and 7-positions. Acenocoumarol enantiomers were much better substrates for cytochromes P-450 than the corresponding warfarin enantiomers; Km values for the 6- and 7-hydroxylations were 2 to 19 times lower for R- and S-acenocoumarol than for warfarin. 2. Formation of the 6-, 7-, and 8-hydroxy-metabolites of warfarin was stereoselective for the R-enantiomer (the R/S ratio for total intrinsic clearance was about 3). 4'-Hydroxylation was not stereoselective. In contrast, formation of acenocoumarol metabolites was stereoselective for the S-enantiomer (the S/R ratio for total intrinsic clearance was about 3). 3. From the effects of phenobarbitone and methylcholanthrene induction, and inhibition by cimetidine, on in vitro metabolism of the enantiomers of both compounds, it was concluded that the differences between warfarin and acenocoumarol can be explained partly by the involvement of different enzymes.     

Stereoselective aspects in the pharmacokinetics and pharmacodynamics of acenocoumarol and its amino and acetamido derivatives in the rat

The stereoselectivity of the pharmacokinetics and of the pharmacodynamics of the oral anticoagulant acenocoumarol (AC) and of two of its potential metabolites, the amino (AM) and the acetamido (AA) derivatives, were investigated in the rat. The pharmacokinetics and pharmacodynamics were investigated following the acute subcutaneous (1 mg/kg) administration of the pure enantiomers. For AC and AA, the S(-)-enantiomer was preferentially eliminated, whereas for AM the R(+)-enantiomer showed the shortest half-life. The differences in elimination between the AC enantiomers were entirely due to differences in total clearance, 183 +/- 14 and 714 +/- 148 ml X h-1 X kg-1 (+/- SD) for R(+)- and S(-)-AC. Also the differences in elimination between the AM enantiomers were mainly due to differences in body clearance, 50 +/- 13 and 18 +/- 4 ml X h-1 X kg-1 for R(+)- and S(-)-AM. For S(-)-AA the higher total clearance as well as the smaller volume of distribution accounted for its 2-fold higher rate of elimination. Acetylation of AM, i.e. the conversion to AA, which accounted for about 50% of its total clearance was stereoselective for R(+)-AM. The renal clearance of AA which accounted for 50-60% of the AA clearance was not selective for one of the AA enantiomers. Stereoselectivity in plasma protein binding was observed, the differences, however, were small. Thus, stereoselectivity in plasma protein binding did not account for the observed differences in the pharmacokinetics. The differences in anticlotting activity between the enantiomers of AC and AM were determined mainly by their pharmacokinetics.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disposition of flurbiprofen in man: influence of stereochemistry and age

1. The stereoselective metabolism and pharmacokinetics of the enantiomers of flurbiprofen were investigated following the oral administration of the racemic drug (100 mg) to four young and four elderly healthy volunteers (two males and two females per group). 2. The stereochemical composition of the drug and the 4'-hydroxy- metabolite in serum and the drug, 4'-hydroxy- and 3'-hydroxy-4'-methoxy- metabolites, both free and conjugated, in urine were determined by a direct chromatographic method of enantiomeric analysis. 3. Modest enantioselectivity in clearance (CL S/R: young, 0.86; elderly, 0.88) was largely responsible for the apparent elimination half-life of (S)-flurbiprofen being significantly greater (p<0.01) than that of the R-enantiomer in both age groups (young, S: 5.2 +/- 0.7 versus R: 4.5 +/- 0.6 h; elderly, S: 9.6 +/- 1.2 versus R: 7.1 +/- 1.0 h). The serum concentrations of 4'-hydroxyflurbiprofen were five- to 20-fold lower than those of the corresponding drug enantiomers, stereoselective disposition being evident in the significantly greater (p<0.05) apparent half-lives of the S- compared with the R-enantiomer in both groups (young, S: 10.6 +/- 2.4 versus R: 6.7 +/- 1.1 h; elderly, S: 13.7 +/- 1.7 versus R: 10.2 +/- 1.2 h). 4. Some 60 and 72% of the dose was excreted in 24-h urine in elderly and young volunteers, respectively, a significantly greater (p<0.05) proportion of which was of the R-configuration in both age groups (S/R: young, 0.87; elderly, 0.81). The major urinary excretion products were flurbiprofen and 4'-hydroxyflurbiprofen, and their acyl-conjugates in both groups. 5. Age-associated differences in the pharmacokinetics of flurbiprofen occurred in a non-stereoselective manner and were primarily as a consequence of a significant approximately 40% decrease (p<0.01) in clearance of both enantiomers in the elderly due to reduced metabolic activity. Consequently, the elderly had greater exposure to both enantiomers, as reflected by the AUCs(0-inf) being significantly higher (p<0.05), by 60%, in this age group compared with the young. 6. The findings suggest that age-related alterations in the disposition of flurbiprofen could have significant implications for the use of the drug in the elderly.     

Effect of aging on the pharmacokinetics of acebutolol enantiomers.

Acebutolol (AC) is a chiral beta-blocker that is metabolized to an equipotent chiral metabolite, diacetolol (DC). A stereoselective disposition of AC and DC enantiomers has recently been reported in young healthy subjects. As many physiologic properties affecting drug disposition are progressively altered with increasing age, the effect of aging on the pharmacokinetics of AC and DC enantiomers were investigated in nine subjects ranging from 60 to 75 years after administration of an oral 200-mg dose of racemic AC. Increasing age resulted in a significant prolongation of the elimination t1/2s of R- (r = 0.913) and S-DC (r = 0.811). Also, the S:R ratios of AC urinary excretion (sigma Xu) of enantiomers was significantly correlated with age (r = 0.677). Contribution of declining renal function to age-associated pharmacokinetics changes was subsequently examined. Renal clearance and cumulative urinary excretion of both AC and DC enantiomers were positively correlated with creatinine clearance. In addition, declining creatinine clearance was associated with a subsequent decline in the enantiomer S:R ratio of AC in plasma (AUC S:R, r = 0.807) and urine (sigma Xu S:R r = 0.807). Similarly, a progressive decline in the S:R ratio of DC collected in urine was evident (r = 0.689). Age-related changes in the enantiomers ratios may suggest that an active stereoselective pathway such as renal tubular secretion or nonrenal excretion may be affected in the elderly.     

PHARMACOKINETICS AND MULTIPLE PEAKING OF ACEBUTOLOL ENANTIOMERS IN RATS

Acebutolol (AC) is a chiral β-blocker which is extensively metabolized to an active, chiral metabolite, diacetolol (DC). Similar to some other β-adrenoceptors, AC exhibits multiple peaks in plasma concentration–time curves after oral doses to humans. We examined the suitability of the rat as an animal model and studied the effect of various factors including the route of administration, food, and bile on the pharmacokinetics of AC enantiomers. Pharmacokinetics of AC were delineated after oral (fed and fasted), iv, and ip doses, and after oral and iv doses, to intact and bile-duct-ligated female Sprague–Dawley rats, respectively. The possibility of intestinal metabolism or saturable absorption was studied in vitro using everted rat gut. Multiple peaks were present but only after oral doses independent of food intake, suggestive of gastrointestinal tract involvement. Oral absorption of AC enantiomers was incomplete as bioavailability was lower after oral (R, 0·59; S, 0·63) as compared to ip (R, 0·86; S, 0·84) doses. Food reduced bioavailability by 60%. A 250-fold increase in the dose did not alter the absorption kinetics of AC through the everted gut, ruling out the possibility of saturable absorption. No intestinal metabolism was detected in vitro. Enterohepatic recirculation cannot be responsible as ligation of the bile duct did not alter the pattern or route dependence of the multiple peaking. The rat appears to be a suitable animal model; a bile- and food-independent erratic absorption is probably responsible for the observed multiple peaking of AC. © 1997 John Wiley & Sons, Ltd.     

Preclinical stereoselective disposition and toxicokinetics of two novel MET inhibitors

The R- and S-enantiomer of N-(4-(3-(1-ethyl-3,3-difluoropiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide are novel MET kinase inhibitors that have been investigated as potential anticancer agents. The effect of the chirality of these compounds on preclinical in vivo pharmacokinetics and toxicity was studied. The plasma clearance for the S-enantiomer was low in mice and monkeys (23.7 and 7.8 mL min(-1) kg(-1), respectively) and high in rats (79.2 mL min(-1) kg(-1)). The R/S enantiomer clearance ratio was 1.5 except in rats (0.49). After oral single-dose administration at 5 mg kg(-1) the R/S enantiomer ratio of AUC(inf) was 0.95, 1.9 and 0.41 in mice, rats and monkeys, respectively. In an oral single-dose dose-ranging study at 200 and 500 mg kg(-1) and multi-dose toxicity study in mice plasma AUC exposure was approximately 2- to 3-fold higher for the R-enantiomer compared to the S-enantiomer. Greater toxicity of the S-enantiomer was observed which appeared to be due to high plasma C(min) values and tissue concentrations approximately 24 h after the final dose. Both enantiomers showed low to moderate permeability in MDCKI cells with no significant efflux, no preferential distribution into red blood cells and similar plasma protein binding in vitro. Overall, the differences between the enantiomers with respect to low dose pharmacokinetics and in vitro properties were relatively modest. However, toxicity results warrant further development of the R-enantiomer over the S-enantiomer.     

Evidence for Intestinal Secretion as an Additional Clearance Pathway of Talinolol Enantiomers: Concentration- and Dose-dependent Absorption in Vitro and in Vivo

Purpose. To evaluate carrier-mediated intestinal secretion of talinolol enantiomers in vivo and in vitro. Methods. In clinical studies with i.v. and p.o. dosage of rac-talinolol (30 mg and 100 mg, resp.) performed in a small number of cholecystectomized patients total and partial clearances were determined on the basis of plasma, bile and urine concentrations. The dose-dependence of AUC was investigated in 12 healthy volunteers (25, 50, 100, and 400 mg rac-talinolol as single p.o. doses). Concentration-dependence of the permeability across Caco-2 cell monolayers included concentrations from 0.1 to 2.0 mM, inhibition by verapamil was tested at 0.5 mM. Results. The total clearance as well as the apparent oral clearance (CL/F) were slightly higher for S-(–)-than for R-(+)-talinolol. Calculation of the partial clearances showed that also the residual clearance was higher for the S- than for the R-enantiomer. In the healthy volunteers, CL/F increased with increasing doses, while the S/R ratio decreased approaching unity for the highest dose. Also the results from Caco-2 cell permeation studies yielded a clear concentration-dependence with decreasing stereoselectivity for the higher concentration range. Permeability of both enantiomers was considerably higher for ba than ab transport, however, this difference disappeared when verapamil was added. Conclusions. Although not very expressed, the detected stereoselectivities indicate a preferential absorption of R-(+)-talinolol in a lower concentration and dose range, which is most probably due to a moderate stereoselectivity at the carrier system involved in intestinal secretion.     

Enantioselective pharmacokinetics of etodolac in the rat: tissue distribution, tissue binding, and in vitro metabolism.

The nonsteroidal anti-inflammatory agent etodolac (ET) exhibits stereoselectivity in its pharmacokinetics following administration to humans and rats. To underline the factors responsible for this stereoselectivity, the tissue distribution, in vitro tissue binding, and microsomal metabolism of ET enantiomers were studied in the rat. Following iv administration of racemic ET, the S:R AUC ratios in tissues were stereoselective, and different from that in plasma. Binding of enantiomers to tissues was stereoselective, although it did not relate well with in vivo tissue distribution. Rather, the tissue distribution of enantiomers appeared to be better explained by the unbound fractions of enantiomers in plasma. With respect to in vitro glucuronidation by liver microsomes, the Vmax of S-ET was 3.4-fold greater than that of R-ET; the enantiomers possessed similar Km. There appeared to be stereoselectivity in the oxidative metabolism of ET enantiomers by liver and kidney microsomes, in favor of the R-enantiomer. The lower AUC in rat plasma of pharmacologically active S-ET as compared with its antipode is due to its relatively greater distribution to tissues, owing to a lesser degree of binding to plasma proteins, and to its higher rate of glucuronidation.     

Disposition of the enantiomers of hydroxychloroquine in patients with rheumatoid arthritis following multiple doses of the racemate.

In eight patients with rheumatoid arthritis receiving racemic hydroxychloroquine, blood and urine concentrations of the enantiomers of hydroxychloroquine and its major metabolites were measured each month over the first 6 months of therapy. Plasma concentrations of hydroxychloroquine enantiomers were measured in five of these patients. In all patients, the blood concentration of (R)-hydroxychloroquine exceeded that of the (S)-enantiomer, the mean (R)/(S) ratio being 2.2 (range 1.6-2.9). A similar excess of (R)-hydroxychloroquine was found in the plasma, the mean (R)/(S) ratio being 1.6 (range 1.2-1.9). The mean enantiomer blood concentration ratio (R)/(S) for the metabolite desethylhydroxychloroquine was 0.45 (range 0.34-0.58) and for desethylchloroquine it was 0.56 (range 0.35-0.86) suggesting stereoselective metabolism of hydroxychloroquine. (S)-hydroxychloroquine had a mean (+/- s.d.) renal clearance from blood of 41 +/- 11 ml min-1, approximately twice that of (R)-hydroxychloroquine. The predicted unbound renal clearance was also higher for (S)-hydroxychloroquine. The clinical implications of enantioselective disposition of hydroxychloroquine are currently not known.     

Enantioselective Kinetics of Verapamil and Norverapamil in Isolated Perfused Rat Livers

The kinetics of the individual enantiomers of verapamil (VER) and its metabolite, norverapamil (NOR), were studied in isolated perfused rat livers (IPRLs) after administration of racemic drug or the preformed metabolite. After constant infusion of 20 µg/min of racemic VER to single-pass IPRLs, the hepatic availabilities (F) of the enantiomers were low (S-VER, 0.069 ± 0.030; R-VER: 0.046 ± 0.025) and stereoselective (S:R ratio, 1.6 ± 0.2). After administration of similar doses, the F values of the preformed NOR enantiomers (S-NOR: 0.24 ± 0.04; R-NOR, 0.10 ± 0.02) were higher than those of the VER enantiomers. However, the stereoselectivity in F of NOR (S:R ratio, 2.2 ± 0.1), was in the same direction of that of VER. Further, the fractions of R enantiomers unbound to bovine serum albumin in the perfusate were higher than those of their antipodes for both VER (R:S ratio, 1.9 ± 0.1) and NOR (R:S ratio, 2.6 ± 0.2). Therefore, for unbound moieties, modest stereoselectivity in the metabolism of VER in favor of the S-isomer and no stereoselectivity in the metabolism of NOR were observed. Overall, our data suggest that the stereoselective protein binding is a primary determinant of stereoselectivity in the hepatic availability of VER and NOR in IPRLs.     

Stereoselective pharmacokinetics and pharmacodynamics of verapamil and norverapamil in rabbits.

We have estimated the pharmacokinetic and pharmacodynamic interactions of verapamil (VP) enantiomers and also the interaction between VP and its metabolite, norverapamil (NVP). ECGs of conscious rabbits were studied to determine the pharmacokinetics of VP enantiomers and racemic NVP in relation to their prolongation effect on PR intervals, which were used as an index of VP's antiarrhythmic effect. Plasma free fractions of VP enantiomers showed constant values at concentrations ranging from 0.022 to 1.10 microm. There were no interactions between enantiomers or between VP and NVP. The pharmacological effect of the S-enantiomer (S-VP), which was determined by linear regression analysis, showed it was about 20 times more potent than that of the R-enantiomer (R-VP). The effect of racemic VP was the simple sum of those elicited by both enantiomers. These relationships were not significantly different between intravenous infusion and bolus injection. Simultaneous intravenous infusion of NVP had no influence on the PR intervals. In conclusion, we demonstrated that the relationship between plasma unbound concentration of VP enantiomers and their pharmacological effect was the simple sum of two enantiomers.     

普罗帕酮对映体在汉族志愿者体内药动药效学研究

目的研究普罗帕酮对映体在中国汉族健康志愿者体内的相互作用。方法以双盲、随机、安慰剂对照的方法,比较汉族健康志愿者口服（Ｒ／Ｓ）－,（Ｓ）－和（Ｒ）－普罗帕酮（ＰＰＦ）（１５０ｍｇ,ｑ６ｈ,×４ｄ）后对最大运动心率（ＨＲｍａｘ）,ＰＲ,ＱＲＳ,ＱＴｃ间期及平均动脉压（ＭＢＰ）的影响,并测定服（Ｒ／Ｓ）－ＰＰＦ及对映体后（Ｒ）－和（Ｓ）－ＰＰＦ的血药浓度。结果服对映体后,（Ｓ）－ＰＰＦ的血药浓度低于（Ｒ）－ＰＰＦ,而服（Ｒ／Ｓ）－ＰＰＦ后,（Ｓ）－ＰＰＦ血药浓度高于（Ｒ）－ＰＰＦ。与安慰剂相比,（Ｒ／Ｓ）－和（Ｓ）－ＰＰＦ显著减慢ＨＲｍａｘ,ΔＨＲｍａｘ分别为（－９．８±８．０）次·ｍｉｎ－１（Ｐ＜０．０５）,（－８．４±６．８）次·ｍｉｎ－１（Ｐ＜０．０５）,安慰剂ΔＨＲｍａｘ为（１．５±８）次·ｍｉｎ－１。（Ｒ）－ＰＰＦ不影响ＨＲｍａｘ,ΔＨＲｍａｘ为（０．５±７．５）次·ｍｉｎ－１。（Ｒ／Ｓ）－,（Ｓ）－和（Ｒ）－ＰＰＦ对ＰＲ,ＱＲＳ和ＱＴｃ间期的影响两对映体间及与消旋体间差异均无显著性。三者对ＭＢＰ无显著作用。结论在中国汉族人体内,（Ｓ）－ＰＰＦ与（Ｒ）－ＰＰＦ间存在与白种人相似的相互作用,这种相互作用?