Enantioselective disposition and protein binding of [(5,6-dichloro-9a-propyl-3-oxo-2,3,9,9a-tetrahydro-1-H-fluoren-7 -yl)-oxy] acetic acid, a new cerebral antiedemic agent, in rats

[(5,6-Dichloro-9a-propyl-3-oxo-2,3,9,9a-tetrahydro-1-H-fluoren-7-y l)-oxy] acetic acid (DPOFA) is an agent capable of reducing the swelling of astroglial cells in brain tissues. In vitro studies have demonstrated that the (R)-(+)-form of DPOFA is more effective than its (S)-(-)-form in inhibiting tissue swelling. The purpose of this study is to compare the elimination kinetics of the enantiomers. A new stereoselective HPLC procedure was developed for the simultaneous quantitation of (R)-(+)- and (S)-(-)-enantiomers in plasma and bile samples. After iv administration of the racemic mixture (40 mg/kg), rats cleared the (R)-(+)-enantiomer more rapidly than the (S)-(-)-isomer; time-averaged total plasma clearances were 8.88 +/- 0.55 and 4.20 +/- 0.70 ml/min/kg (mean +/- SD), respectively. Similar results were observed when the individual isomers were administered (20 mg/kg iv). Both (R)-(+)- and (S)-(-)-enantiomers were highly bound to plasma protein. The (R)-(+)-isomer had a higher unbound fraction (2%) than did the (S)-(-)-enantiomer (0.8%). The intrinsic clearance of unbound drug for (R)-(+)- and (S)-(-)-enantiomers were 434 +/- 27 and 490 +/- 84 ml/min/kg, respectively, suggesting that the differences in the elimination of the enantiomers in rats were attributable to stereoselectivity in plasma protein binding rather than to enzyme activity. In vitro studies with isolated hepatocytes supported the hypothesis that there was no stereoselectivity in metabolism of the enantiomers.     

Stereoselective pharmacokinetics of a novel uricosuric antihypertensive diuretic in rats: pharmacokinetic interaction between enantiomers.

5-Dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxyli c acid (DBCA), a promising uricosuric, diuretic, and antihypertensive agent, was administered intravenously to rats. The levels of DBCA in plasma and the areas under the curve of concentration versus time (AUC values) of the S(-)-enantiomer were higher than those of the R(+)-enantiomer. Total body clearance was significantly greater for the R(+)-enantiomer. This stereoselective elimination was due to a difference in the nonrenal clearance, which seemed to reflect hepatic metabolism or biliary excretion. Hepatic metabolism seemed more likely because AUC and the amount of urinary excretion of the N-monodemethylated metabolite of DBCA were greater for the R(+)-enantiomer. The plasma had higher free fractions of the S(-)-enantiomer, a result suggesting that this enantiomer is distributed more readily to the tissues, including the liver. This result indicates that protein binding was not responsible for the stereoselective metabolism of (R)-(+)-DBCA. Although there was no difference in the renal clearances of the enantiomers, the renal clearance of free (R)-(+)-DBCA exceeded that of the S(-)-enantiomer, a result indicating the preferential excretion of the R(+)-enantiomer into the urine. Comparison of the pharmacokinetics of individual enantiomers after intravenous administration of each enantiomer or its racemate showed that the enantiomers interact with one another; dosing with racemate delayed the elimination of each enantiomer because of mutual inhibition of hepatic metabolism and renal excretion for (R)-(+)-DBCA and of renal excretion for (S)-(-)-DBCA.     

Stereoselective disposition of mexiletine in man.

The pharmacokinetics of S-(+)- and R-(-)-mexiletine and of the corresponding conjugates were investigated in six healthy young volunteers after administration of a single 200 mg oral dose of racemic mexiletine hydrochloride. The values for the distribution rate constants as well as for the elimination half-lives of the two enantiomers were similar but the AUC of the S-(+)-enantiomer was always significantly higher (P less than 0.01) than that of the opposite enantiomer. The mean R/S ratios for unchanged mexiletine in serum and in urine were 0.78 +/- 0.12 (s.d.) and 0.80 +/- 0.21, respectively. Urinary excretion of mexiletine conjugates consisted mainly of the R-(-)-enantiomer; the mean R/S enantiomeric ratio over 48 h was 9.65 +/- 3.10. Serum concentrations of the conjugates were measured in three subjects. The mean R/S AUC ratio was 2.94 +/- 0.48 and the renal clearance of the R-(-)-enantiomer was significantly higher (P less than 0.02) than that of the S-(+)-enantiomer.     

Species-dependent stereopharmacokinetics of MK-927, a potent carbonic anhydrase inhibitor.

MK-927 [5,6-dihydro-4H-4(isobutylamino)thieno(2,3-B)thiopyran-2-sul fonamide -7,7 dioxide], a potent carbonic anhydrase inhibitor, contains a chiral center and is a mixture of two forms, R-(-)- and S-(+)-enantiomer. The latter has recently been designated as MK-417. Following iv administration of each enantiomer (0.05 mg/kg), dogs, rabbits, and rats cleared the R-(-)-enantiomer more rapidly than the S-(+)-enantiomer. The elimination clearance of the R-(-)-enantiomer was 2.01 +/- 0.34, 30.0 +/- 2.1, and 53.6 +/- 6.4 ml/hr/kg for dogs, rabbits, and rats, respectively. The corresponding values for the S-(+)-isomer were 0.0380 +/- 0.008, 1.15 +/- 0.20, and 1.29 +/- 0.09 ml/hr/kg. The ratio of the clearance of the R-(-)-enantiomer to that of the S-(+)-isomer was approximately 53 for the dog, 42 for the rat, and 26 for the rabbit, indicating that the degree of stereoselectivity in elimination kinetics of MK-927 enantiomers was species-dependent. Binding of the enantiomers to erythrocytes, presumably carbonic anhydrase, was also stereoselective and species-dependent; the S-(+)-enantiomer was bound more strongly than the R-(-)-isomer in all species. For both enantiomers, binding to carbonic anhydrase was found to be more extensive in dogs than in other species studied. The elimination clearance of the enantiomers in all species was roughly related to their binding affinity, greater Kd1 values being associated with more rapid clearance. However, binding data alone cannot quantitatively explain the degree of the species-dependent stereoselectivity in the elimination kinetics; other factors may also contribute.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stereoselective metabolism of carvedilol in the rat. Use of enantiomerically radiolabeled pseudoracemates.

14C-Labeled R(+)- and S(-)-carvedilol enantiomers were prepared by direct resolution of 14C-labeled racemic carvedilol on a chiral HPLC column. Two enantiomerically radiolabeled carvedilol pseudoracemates, 14C-labeled R(+)/unlabeled S(-)-carvedilol and 14C-labeled S(-)/unlabeled R(+)-carvedilol, were reconstituted and administered orally and iv to separate groups of bile duct-cannulated rats to determine the biliary excretion of carvedilol enantiomers and the stereochemical composition of metabolites excreted into the bile. The respective biliary excretions of the radioactivity derived from the radiolabeled R(+)- and S(-)-enantiomers accounted for 41.4 +/- 0.9 and 41.5 +/- 1.9% of the oral racemic dose, and 43.7 +/- 2.4 and 40.0 +/- 0.9% of the iv dose. Oral administration of these pseudoracemates produced no enantiomeric difference in the biliary excretion of the radioactivity derived from the enantiomers, whereas iv administration did result in an enantiomeric difference: the biliary excretion rate of the radioactivity derived from R(+)-enantiomer was higher than that from S(-)-enantiomer. After administration by the two routes, two carbazole ring-hydroxylated glucuronides, 1-hydroxycarvedilol O-glucuronide (1-OHCG) and 8-hydroxycarvedilol O-glucuronide (8-OHCG), were detected as the major metabolites in the bile. The S/R enantiomer ratios of 1-OHCG were 0.59 for oral dosing and 0.43 for iv dosing, suggesting that the formation of 1-OHCG is selective for R(+)-enantiomer, while the S/R ratios of 8-OHCG showed values of 3.29 and 2.63 for oral and iv administrations, respectively, favoring S(-)-enantiomer. Since corresponding hydroxylated metabolites are rapidly biotransformed to glucuronides that are excreted predominantly in the bile, the stereoselectivity of these glucuronides presumably reflects that of carbazole ring hydroxylation.     

Pharmacokinetics of atenolol enantiomers in humans and rats

Single dose pharmacokinetics of atenolol (AT) enantiomers was studied in human volunteers and in rats. After oral administration of 50 mg of racemic AT to humans, the areas under the plasma concentration-time curves (AUCs; mean +/- SD) were 1640 +/- 602 and 1860 +/- 652 (ng/mL)h for the S(-)- and R(+)-enantiomers, respectively (p less than 0.05). The small difference in the AUC was a reflection of a slight, but statistically significant (p less than 0.05) difference in the renal clearance (CLr, mL/min) of the enantiomers [129 +/- 32, S(-)-AT; 120 +/- 29, R(+)-AT]. However, the two enantiomers were not different from each other (p greater than 0.05) with respect to the volume of distribution (V lambda, L/kg) [0.879 +/- 0.342, S(-)-AT; 0.790 +/- 0.255, R(+)-AT] or the terminal elimination rate constant (lambda z, h-1) [0.113 +/- 0.038, S(-)-AT; 0.114 +/- 0.036, R(+)-AT]. After iv administration of 10 mg/kg of the racemic AT to rats, the R(+)-enantiomer achieved higher AUC values [(ng/mL)h] compared with its antipode (p less than 0.05) [3630 +/- 1040, S(-)-AT; 4020 +/- 1080, R(+)-AT]. Similar to the human results, this difference was due to a stereoselective renal clearance (mL/min/kg) in favor of S(-)-AT [14.9 +/- 5.78, S(-)-AT; 13.0 +/- 4.88, R(+)-AT; p less than 0.05].(ABSTRACT TRUNCATED AT 250 WORDS)     

Dose-dependent stereopharmacokinetics of 5,6-dihydro-4H-4(isobutylamino)thieno(2,3-B)thiopyran-2-sulfonamide-7,7 -dioxide , a potent carbonic anhydrase inhibitor, in rats.

[5,6-dihydro-4H-4(isobutylamino)thieno(2,3-B)thiopyran-2-sul fonamide-7,7- dioxide] (MK-927), a potent carbonic anhydrase inhibitor capable of reducing intraocular pressure after topical application, is currently under investigation for the treatment of glaucoma. The purpose of this study was to characterize the pharmacokinetics of the enantiomers of MK-927 with particular emphasis on the effect of dose on the elimination kinetics. Because the drug resided primarily in erythrocytes, the kinetic analysis was generally performed based on the drug concentration of whole blood. Following iv administration, the rat cleared the (R)(-)-enantiomer more rapidly than the (S)(+)-isomer. The stereoselective difference in elimination kinetics was dose-dependent; total blood clearance of the (R)(-)-enantiomer was approximately 40 times that of the (S)(+)-isomer at 0.05 mg/kg, and about 7-fold at 5 mg/kg. For both enantiomers, the pharmacokinetic parameters remained unchanged when the dose increased from 0.05 to 0.2 mg/kg, while the total blood clearance and apparent volume of distribution increased substantially as the dose exceeded 2 mg/kg. Nevertheless, the terminal half-life for each enantiomer appeared to be dose-independent. The enantiomers were extensively bound to erythrocytes in a stereoselective manner; at low concentrations, the (S)(+)enantiomer was bound 3-fold more strongly than the (R)(-)-enantiomer in vitro and 6-fold in vivo. Clearly, the magnitude of stereoselectivity in the elimination kinetics of MK-927 enantiomers (40-fold) cannot be explained solely by stereoselective binding. Thus, other factors may also contribute to the overall stereoselectivity in the elimination kinetics of MK-927. The dose-dependent kinetics of the enantiomers was probably due to the saturable binding to carbonic anhydrase.     

Stereoselective disposition of indoprofen in surgical patients.

The pharmacokinetics of the enantiomers of indoprofen were determined after intravenous administration of the racemate to 10 surgical patients. The mean volume of distribution was 8.97 +/- 2.21 (s.d.) 1 for the pharmacologically active S(+)-enantiomer and 12.60 +/- 4.21 1 for the R(-)-enantiomer (P less than 0.001). The corresponding values for clearance were 32.2 +/- 11.1 ml min-1 and 48.8 +/- 15.5 ml min-1 (P less than 0.001). There was no significant difference in mean terminal half-life between the enantiomers.     

The pharmacokinetics of the enantiomers of mexiletine in humans

1. This study examined the pharmacokinetics of the enantiomers of mexiletine in five healthy subjects who were each given a single, 300 mg, oral dose of racemic mexiletine hydrochloride. 2. The time course of the concentration ratio between the R(-) and the S(+) enantiomers (R/S) in plasma showed a progressive decrease, with a mean +/- S.D. ratio of 1.37 +/- 0.11 at 1 h and 0.64 +/- 0.11 at 48 h. Similarly, the R/S ratios in urine were 1.38 +/- 0.42 and 0.55 +/- 0.12 at 1 h and 72 h, respectively. 3. The terminal elimination half-life of S(+)mexiletine was 11.0 +/- 3.80 h, which was significantly greater (P less than 0.05) than that of the R(-) enantiomer, 9.10 +/- 2.90 h. S(+)Mexiletine also showed a significantly greater apparent volume of distribution (P less than 0.01) and renal clearance (P less than 0.05) than R(-)mexiletine. There was no significant difference in the apparent oral total drug clearance of the enantiomers. 4. The disposition of mexiletine enantiomers in man was stereoselective, and the differences observed between the enantiomers may be due largely to differences in their serum protein binding.     

Stereoselective drug distribution and anticoagulant potency of the enantiomers of phenprocoumon in rats.

The elimination, distribution and anticoagulant activity of S(-)-, R(+)-, and R,S(+/-)- phenoprocoumon were determined in male Wistar-Lewis rats after intravenous injection of a single dose of 0.6 mg kg-1. From the plasma concentrations which elicited the same anticoagulant effect, S(-)-phenprocoumon was 4 to 5 times more potent than R(+)-phenprocouman. The potency of the racemate was between those of the enantiomers. The mean biologic half-life of the S(-)-enantiomer was shorter (12-5 h) than that of R(+)-phenprocoumon (17-8 h). No differences were observed in the apparent volume of distribution. However, the mean liver:plasma concentration ratio was higher for the S(-)-(6-9) than for the R(+)-enantiomer (5-2). At a total concentration of 16-8 microgram ml-1 the percentage of unbound drug in rat serum was significantly higher for the S(-)- (1-13%) than that for the R(+)-enantiomer (0.76%). Values obtained for the racemate were always between those of the enantiomers. It is concluded that stereoselective differences in the distribution between plasma and liver, and consequently in the rate of elimination are most likely due to stereoselective differences in serum protein binding. The greater anticoagulant potency of the S(-)- over the R(+)-enantiomer, cannot be explained primarily by the observed pharmacokinetic differences.     

The stereoselective pharmacokinetics of etodolac in young and elderly subjects, and after cholecystectomy.

The pharmacokinetics of the enantiomers of etodolac were studied in six young subjects (ages 28 +/- 3.3 years), 6 nonarthritic elderly subjects (ages 73 +/- 6.0 years), and in three cholecystectomy patients after single oral doses of the racemate (200 mg). In all subjects, the plasma concentrations of R-etodolac, which is pharmacologically inactive, greatly exceeded those of the pharmacologically active S-enantiomer. Stereoselectivity was reflected in the pharmacokinetics, with R > S for maximum peak plasma concentration and area under the concentration versus time curve, and S > R for apparent oral clearance and apparent volume of distribution. On average, less than 25% of the dose of each enantiomer was excreted in the urine within 24 hours as alkali-labile conjugates; little or no unchanged drug was recovered. Bile constituted a minor route of elimination of etodolac as conjugated enantiomers. There were no significant differences in the pharmacokinetics of etodolac enantiomers between the young and elderly subjects. The results reflect the importance of considering stereoselectivity in evaluating the pharmacokinetics of etodolac.     

Stereoselective disposition of S-8666, a novel uricosuric antihypertensive diuretic, and its N-monodemethylated metabolite in a perfused rat liver preparation. Effect of protein binding on the kinetics of S-8666.

S-8666 (5-dimethyl-sulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid), a novel uricosuric antihypertensive diuretic, and its N-monodemethylated metabolite (M-I) were studied in a single pass perfused rat liver preparation under constant perfusate flow (ca. 16 ml/min). During perfusion with 100 nmol/ml of racemic S-8666 not containing bovine serum albumin (BSA), the steady-state hepatic extraction ratio of R(+)-S-8666 was two times higher (0.65 +/- 0.08) than that of S(-)-S-8666 (0.34 +/- 0.08). R(+)- and S(-)-M-I in the effluent perfusate plasma accounted for 64 and 18% of the influx rate of each enantiomeric S-8666, respectively. The N-monodemethylation was found to be responsible for the hepatic extraction of S-8666 enantiomers. S(-)-S-8666 was excreted into bile at a more rapid rate than the R(+)-enantiomer. Biliary excretion of R(+)-M-I was faster than S(-)-M-I, although the excretion rates of M-I were slower than those of S-8666 for both enantiomers. The steady-state extractions of preformed R(+)- and S(-)-M-I were low and a significant difference [S(-) greater than R(+)] was observed during the perfusion of 100 nmol/ml preformed racemic M-I without BSA. Increasing the concentration of BSA in the perfusate led to decreases in the extraction ratios of S-8666 enantiomers and biliary excretion rates of all chemicals, which was due to the decreases in the free fractions of S-8666 and M-I enantiomers. The binding of S-8666 and M-I enantiomers to BSA also showed stereoselectivity [R(+) less than S(-)].(ABSTRACT TRUNCATED AT 250 WORDS)     

Stereoselective pharmacokinetics of propafenone and its major metabolites in healthy Chinese volunteers.

The stereoselective pharmacokinetics of propafenone (PPF) and its active metabolite 5-hydroxypropafenone (5-OHP) as well as their glucuronide and sulfate conjugates have been investigated, in order to clarify the relationship between metabolism and stereoselective disposition of PPF in humans. After oral administration of 300 mg racemic PPF hydrochloride to 10 healthy Chinese subjects, the areas under the plasma concentration-time curves (AUCs) for (S)-PPF were significantly higher (S/R ratio, 1.50+/-0.17) and the apparent oral clearance significantly lower (S/R ratio, 0.68+/-0.07) than those parameters for (R)-PPF. In contrast, the AUCs of PPF glucuronide (PPF-G) were lower for (S)-PPF-G than for the (R)-enantiomer (S/R ratio, 0.83+/-0.12). The partial clearance of (S)-PPF by glucuronidation pathway was lower than that of (R)-PPF and the enantiomeric ratio was 0.62+/-0.04. The t(max) values of PPF glucuronide diastereoisomers showed no statistically significant differences between each other, but were much shorter than the corresponding values of the parent drug, implying that glucuronidation may be the 'first-choice' pathway in presystemic metabolism of PPF. Glucuronidation of 5-OHP favored the (S)-enantiomer, whereas the sulfation showed a large preference for the (R)-enantiomer. After beta-glucuronidase hydrolysis, no significant differences were observed in AUCs between 5-OHP enantiomers (including unconjugated and conjugated 5-OHP). The results suggest that the significant difference in disposition between PPF enantiomers may be, at least in part attributed to stereoselective metabolism in the glucuronidation pathway.     

Influence of substrate configuration on chlorpheniramine N-demethylation by hepatic microsomes from rats, rabbits, and mice

Measurements of formaldehyde formation in parallel incubations containing either (S)-(+)- or (R)-(-)-chlorpheniramine (CPA) and rat liver microsomes demonstrated that the active antihistamine, (S)-(+)-CPA, is N-demethylated about 35% faster than the inactive (R)-(-)-enantiomer. The KM values for the enantiomers were the same. Phenobarbital pretreatment increased Vmax values without affecting the stereoselectivity. N-Demethylation occurred at a several-fold faster rate with rabbit than with rat liver microsomes, but stereoselectivity was the same. N-Demethylation of CPA enantiomers were studied in microsomes prepared from each of four inbred strains of mice. These experiments demonstrated that stereoselectivity is species-dependent, as no significant differences in metabolism rates of CPA enantiomers could be detected with these microsomes. Pseudoracemic mixtures containing equal quantities of deuterated (S)-(+)-CPA and unlabeled (R)-(-)-CPA were incubated with microsomes from three species. Formation of the enantiomers of N-desmethyl- and N,N-didesmethyl-CPA (DMCPA and DDMCPA, respectively) were measured by GC/MS techniques. With microsomes from rats and mice, the ratio of (S)-DMCPA to (R)-DMCPA was essentially the same as that determined by measuring the formaldehyde formed in separate incubations of (S)-(+)- or (R)-(-)-CPA. Stereoselectivity with rabbit liver microsomes and pseudoracemic CPA was substantially higher than that determined in incubations with the separate enantiomers. The results suggest either that (S)-(+)-CPA inhibits the N-demethylation of (R)-(-)-CPA under these conditions, or that DMCPA undergoes further biotransformation by a route(s) which is stereoselective, favoring the (R)-enantiomer. Formation of DDMCPA could only be detected with rabbit microsomes and was found to occur with approximately the same stereoselectivity as that determined for the formation of DMCPA.     

Stereoselective metabolism and pharmacokinetics of racemic methylphenobarbital in humans

The stereoselectivity of the metabolism and pharmacokinetics of methylphenobarbital (MPB) was studied in six healthy adult male volunteers given single oral doses of the racemic drug. All of the volunteers were phenotypically extensive metabolizers of the drug. The R- and S-enantiomers of MPB were analyzed in plasma by an enantioselective HPLC method, and the enantiomers of the 4-hydroxy-MPB metabolite in urine by a similar procedure. The (R)-MPB was extensively hydroxylated, with an average of 49.56% of that enantiomer being recovered in urine as (R)-4-hydroxy-MPB. Only 7.16% of the (S)-MPB was converted to the corresponding hydroxy metabolite. The extensive hydroxylation of (R)-MPB resulted in rapid elimination of this enantiomer, with a terminal plasma half-life of 7.52 +/- 1.70 (SD) hr. The (S)-MPB, the only recognized metabolites of which were (S)-4-hydroxy-MPB and phenobarbital (PB), was eliminated very slowly [t1/2, 69.78 +/- 14.77 (SD) hr]. The oral clearance of (R)-MPB (0.470 +/- 0.184 (SD) liters/hr/kg) was much higher than that of (S)-MPB [0.017 +/- 0.001 (SD) liters/hr/kg]. The extreme differences in metabolic fate and pharmacokinetics of the enantiomers of MPB are interesting. Most of the circulating PB seemed to be derived from (S)-MPB. In other respects the pharmacodynamic implications of these pharmacokinetic differences are unclear, because the relative anticonvulsant potencies of the enantiomers of MPB are unknown.     

Tissue distribution of mexiletine enantiomers in rats

1. The kinetics of distribution of the enantiomers of mexiletine were studied in various tissues (heart, brain, lungs, liver, kidneys and fat) in male Sprague-Dawley rats after administration of a single i.v. dose (10mg/kg) of racemic mexiletine.

2. The pharmacokinetic parameters calculated from the serum data showed a 32% greater systemic clearance (162ml/min per kg vs 123 ml/rain per kg) and a 22% greater steady-state volume of distribution (9.01/kg vs 7.4 1/kg) for R(-)-mexiletine relative to the S(+)-enantiomer. However, the terminal elimination half-lives of the enantiomers (1.4 and 1.3h for R(-)- and S(+)-mexiletine, respectively) did not exhibit stereoselectivity.

3. Maximum tissue concentrations of the enantiomers were observed at 5?min after dosage in all tissues studied. Stereoselective uptake was evident only in the liver tissue and was 2.4-fold greater for S(+)-mexiletine. High tissue/serum ratios (>20 for both enantiomers) were observed in lungs, brain and kidneys. The cardiac concentrations of R(-)- and S(+)-mexiletine were 8- and 7-fold those of serum, respectively.

4. The results demonstrate that the uptake of mexiletine enantiomers into the target tissue (heart) is not stereoselective. However, the relatively high brain accumulation of the enantiomers may be related to the CNS side-effects commonly associated with mexiletine therapy.     

Stereoselective pharmacokinetic analysis of the antiepileptic 10-hydroxycarbazepine in dogs

The active entity of the new antiepileptic drug, oxcarbazepine (OXC), is 10-hydroxycarbazepine (MHD). In humans, OXC undergoes rapid presystemic (first-pass) metabolic reduction to MHD. MHD is a chiral molecule with an asymmetric carbon at position 10. Previous reports have shown that in humans, the first-pass metabolic reduction of OXC into MHD is stereoselective, resulting in a 1-to-4 AUC ratio of R(-) and S(+) enantiomers. The objective of the current study was to investigate whether the pharmacokinetics of MHD was stereoselective. Racemic MHD was thus administered intravenously (i.v.) and orally to six dogs, and plasma samples were analyzed by a stereospecific, high-performance liquid chromatographic (HPLC) assay. We found that R(-)-MHD had a clearance similar to that of S(+)-MHD; however, a difference was found between the volume of distribution (Vd) and consequently, between the half-lives of the two MHD enantiomers. The main pharmacokinetic parameters of R(-)- and S(+)-MHD were as follows: A terminal half-life (t1/2) of 2.2 +/- 0.4 hours for R(-)-MHD and of 3.8 +/- 0.3 hours for S(+)-MHD; a clearance (CL) of 7.8 +/- 1.3 L/h for R(-)-MHD and of 8.6 +/- 2.1 L/h for S(+)-MHD; a Vd of 25 +/- 6 L for R(-)-MHD and of 47 +/- 14 L for S(+)-MHD; and a Vd at steady state (V(ss)) of 22.8 +/- 3.6 for R(-)-MHD and of 29.9 +/- 4.1 for S(+)-MHD. After its oral administration to dogs, the absolute bioavailability was 78.4 +/- 20.9% for R(-)-MHD and 78.5 +/- 27.3% for S(+)-MHD; t1/2 was 2.7 +/- 0.6 hours for R(-)-MHD and 4.1 +/- 0.8 hours for S(+)-MHD. These results showed stereoselectivity in the volume of distribution and consequently, the t1/2 of S(+)-MHD was longer than that of R(-)-MHD after both i.v. and oral administration to dogs.     

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.     

Pharmacokinetics of the enantiomers of acenocoumarol in man.

1 The pharmacokinetics of R(+)-, S(-)- and R,S(+/-)-acenocoumarol were studied in healthy volunteers after administration of single oral and intravenous doses. 2 After both oral and i.v. administration of either enantiomer in a dose of 0.25 mg/kg, the concentrations of R(+) found in the plasma were much higher than those of S(-). This indicates that the observed differences are not related to stereoselective absorption. 3 After intravenous administration of 25 mg of each enantiomer and the racemate, the total plasma clearance of S(-) was about 10 times that of R(+). The clearance of the racemate was between that of the enantiomers. 4 The apparent elimination half-life of S(-) was much shorter than those of R(+) and the racemate, which were similar. 5 The apparent volume of distribution VdSS of S(-) acenocoumarol was 1.5 to 2 times that of R(+). 6 Measurements of the extent of binding to serum proteins, made in vitro at much higher concentrations than those observed in vivo, revealed no differences between the two enantiomers and the racemate. 7 The results indicate that the greater anticoagulant potency of R(+) compared with S(-) acenocoumarol can be explained mainly by stereoselective differences in their metabolic clearance.     

Stereoselective disposition of (+/-)-sotalol at steady-state conditions.

The objective of this study was to assess, under steady-state conditions, the stereoselective disposition of (+/-)-sotalol in man. In all patients studied (n = 7) values of oral clearance (137 +/- 51 ml min-1), renal clearance (96 +/- 42 ml min-1) and nonrenal clearance (41 +/- 25 ml min-1) of (-)-sotalol were greater than those for (+)-sotalol (123 +/- 45 ml min-1, 89 +/- 39 ml min-1 and 34 +/- 23 ml min-1, respectively; P < 0.05, Student's paired t-test). Binding to plasma proteins was greater for (+)-sotalol (38 +/- 9% vs 35 +/- 9% for the (-)-enantiomer; P < 0.05) such that unbound oral clearance (+)/(-) ratio (0.95 +/- 0.06) and unbound renal clearance (+)/(-) ratio (0.97 +/- 0.06) were not stereoselective. In contrast, estimated unbound nonrenal clearance, which represents approximately 25% of the total unbound clearance of the drug, was greater for the (-)-enantiomer (64 +/- 42 ml min-1) compared with (+)-sotalol (57 +/- 42 ml min-1; P < 0.05). The difference in the pharmacokinetics of sotalol enantiomers is mainly related to stereoselectivity in plasma protein binding.