Academic Supplement G reat Expectations in St e re o ch e m i s try: Focus on Anti d e p re s s a n t s By C. Lindsay DeVane, PharmD, and David W. Boulton, PhD

ABSTRACT As with all , the physical and chemical character- Chirality has become an increasingly important con- istics of psychoactive agents are major determinants of sideration in the development of psychoactive dru g s their pharmacokinetic pro p e r ties, and there f o re, of the because enantiomers often show major diff e ren ces in their relationship between administered dose or plasma con- p h a r macokinetic and pharmacologic pro p e r ties. This centration and the observed pharmacological eff e c t s . review illustrates the implications of stere o c h e m i s t r y in Over the past decade, stereochemical separation of enan- clinical psychopharmacology using the antidepre s s a n t tiomers has acquired new prominence in psychoactive class of drugs as a focus. In many cases, a better under- d rug development. The purpose of this review is to exam- standing of stere o c h e m i s t r y can improve therapeutic out- ine the implications of the use of single enantiomers ver- comes. For example, with , the racemic sus racemic mixtures in psychiatric re s e a r ch and f o rmulation is effective for depression as well as panic and practice. A focus on the illustrates the obsessive-compulsive disorders. However, the S- e n a n t i o m e r, consequences of chirality in psychoactive drugs norm a l l y , is at least twice as potent as racemic citalo- administered as racemic mixtures. pram as an inhibitor of reuptake, implying that it can be used at lower doses, while offering an impro v e d STEREOCHEMISTRY: therapeutic index as well as an improved safety pro f i l e FUNDAMENTAL CONCEPTS and reduced interaction liability. Clinical trial data The nomenclature and physicochemical pro p e r ties of s u p p o r t these advantages. Continuing re s e a r ch on the s t e reoisomers are reviewed in detail elsewhere in this sup- s t e reochemical pro p e r ties of psychoactive drugs should plement. For the purposes of this discussion, bear in mind simplify the characterization of dose-response re l a t i o n - that, except for their effects on polarized light, a pair of ships, and clarify the effects of disease states, genetic poly- enantiomers have identical physical pro p e rties (eg, molecu- morphisms, pre g n a n c y, age, and gender on stere o s e l e c t i v e lar weight, solubility, and melting point) and have tradition- p h a rmacokinetics and pharmacodynamics. Better under- ally been very difficult to separate. standing of the fate of chiral psychotropic agents and the Some psychoactive drug molecules have more than one factors that influence their stereoselective disposition and chiral center, existing as two or more pairs of enan- actions will provide a rational basis for their expanded use tiomers. Each pair is described as a diastereoisomer of in various patient populations. the other pair(s) and their chemical names follow the C N S S p e c t rums. 2002;7(suppl 1):28-33 same system used for single chiral center molecules (eg, ( + ) - (R , R )-). Because each pair of enan- INTRODUCTION tiomers normally has diff e r ent physicochemical pro p e r - S t e r e o c h e m i s t r y or chirality is an incre a s i n g l y ties than the other pair(s), diastereoisomers are re l a t i v e l y i m p o r tant consideration in pharmaceutical develop- easy to separate chemically. ment, because many drug molecules exist as stere o i s o - S t e r eoisomers are often recognized as being diff e r e n t mers (enantiomers) with distinctly diff e r ent biological chemicals by biological systems and, as a result, tend to p r o p e r ties. Some naturally occuring drugs exist as bind with diff e r ent affinities to receptors and enzymes. racemic mixtures (an equal combination of a dru g ’s Thus, it is not uncommon for one stereoisomer of a dru g s t e r eoisomers), and many synthetic drugs are cre a t e d molecule (known as the eutomer) to possess a significant that way because the production scale-up from labora- p h a rmacologic effect while the other stereoisomer (known as t o r y to industrial quantities often proceeds most expe- the distomer) may lack similar pharmacologic effects, or diently using methods that result in racemic mixture s . may produce diff e ren t effects. Because stereoisomers inter- The separation of these mixtures into individual enan- act diff e ren tly with biological proteins, they may also diff e r tiomers is seldom cost-effective due to difficulties in in their absorption, metabolism, protein binding, and excre- their separation. tion, leading to major diff e rences in their pharm a c o k i n e t i c s

D r. DeVane is professor of psychiatry and behavioral sciences in the Department of Psychiatry at the Medical University of South Carolina in Charleston, where he directs the Laboratory of Drug Disposition and Pharm a c o g e n e t i c s . D r. Boulton was a postdoctoral fellow at the time of this writing, and is currently a re s e a rch scientist for Bristol-Myers Squibb in Princeton, NJ. M e d Works Media 28 April 2002 Academic Supplement and pharmacodynamics. Under these circumstances, a (R)- pre d o m i n a t e s . 1 , 2 O b v i o u s l y, eff o rts to corre- racemic mixture can reasonably be viewed as two separate late pharmacologic effects to the total (R + S ) methadone d rugs, rather than two versions of the same dru g . concentration would produce misleading results: eff i c a c y Many clinically important drugs have at least one asym- might show no relationship to the total concentration, metric or chiral carbon atom and exist as one or more pairs w h e rea s a potentially significant relationship with the level of enantiomers. Familiar examples in psychopharm a c o l o g y of the active enantiomer would be overlooked. include the psychostimulants and The implications of stereoselective pharm a c o k i n e t i c s methylphenidate. Antidepressants that are currently mar- and pharmacodynamics have spurred eff o r ts to develop keted as racemic mixtures are listed in Table 1. pure eutomer formulations. Such formulations would intu- itively be expected to be more potent, to exhibit fewer or Stereoselective Pharmacokinetics less intense side effects, and to have fewer drug interac- and Pharmacodynamics tions than the racemic mixture. In the past, single-isomer A lot has been learned in the past 20 years about the p r oducts were too costly to develop; however, with re c e n t s t e reoselective pharmacokinetics and pharmacodynamics of advances in stereospecific synthesis and analysis, pure chiral drugs. In addition, there have been advances in ana- eutomer formulations are becoming more feasible and lytical methods to separate these drugs into their constituent economical, and single-isomer drugs are now more com- enantiomers. Because disposition of racemic drugs is often monplace. In the field of psychoactive drug development, s t e r eoselective, stereoisomers are rarely present in equal the re s e a r ch eff o r t has yielded several new antidepre s - amounts in the body once administered. Thus, the pharm a- sants with potentially important diff e r ences from their cokinetic and pharmacodynamic data from plasma concen- racemic counterparts. tration measures of total drugs are open to misinterpre t a t i o n . An example from our laboratory of the stere o s e l e c t i v e STEREOCHEMISTRY OF ANTIDEPRESSANTS metabolism of methadone illustrates this point. The pharmacokinetics and pharmacodynamics of Monoamine Oxidase Inhibitors methadone, a chiral synthetic agonist, vary widely Tr a n y l c y p r omine is a non-hydrazine monoamine among patients. Methadone has a single chiral carbon atom oxidase inhibitor (MAOI) with two chiral centers. It is and is marketed as its racemic mixture. The therapeutic a d m i n i s t e r ed as a racemic mixture of the (+)-(1S, 2 R) - and adverse effects of racemic methadone are mostly and (-)-(1R, 2 S)-enantiomers. The (+)-(1S, 2 R) - e n a n - attributable to its R- e n a n t i o m e r, which binds primarily to tiomer is the more potent MAOI of the two, while its the µ-opioid re c e p t o r. The S-enantiomer is about 50-fold antipode inhibits and nore p i n e p h r i n e less potent. Some patients show higher plasma concentra- uptake to some degre e . 3 It is possible that both enan- tions of (R)-methadone, while (S)-methadone pre d o m i n a t e s tiomers contribute synergistically to the antidepre s s a n t in others, and another group shows little or no enantiose- e f fects of . However, pharm a c o k i n e t i c l e c t i v i t y. In addition, there is genetic variability in α1 a c i d data show that plasma and urine concentrations of the g l y c o p rote in, the protein to which methadone is primarily ( + ) - ( 1 S, 2 R)-enantiomer are up to 10-fold higher than bound in plasma. These diff e rences are probably re s p o n s i- those of its antipode, 4 , 5 suggesting that the MAOI ble for the large interindividual variability in therapeutic re s p o n s e . FIGURE. STEREOSELECTIVE DISPOSITION OF An example of enantiomeric disposition of methadone in METHADONE FOLLOWING A SINGLE two healthy volunteers is given in the Figure. The plasma ORAL DOSE OF 0.2 MG/KG OF THE RACEMIC FORMULATION IN TWO concentrations of the enantiomers of methadone are nearly 2 identical in Subject 2, but in Subject 1, the more active H E A LTHY SUBJECTS

TABLE 1. ANTIDEPRESSANTS MARKETED AS RACEMIC MIXTURES

• • Citalopram • • * • * • Tranylcypromine • • • * In subject 1, (R)-methadone (squares) predominates in plasma while in subject 2, (R)-methadone (squares) and (S)-methadone (circles) are nearly *Not available in the United States. equal in concentration. D e Vane CL, Boulton DW. C N S Spectrums. Vol 7, No 4 (suppl 1). 2002. D e Vane CL, Boulton DW. C N S Spectrums. Vol 7, No 4 (suppl 1). 2002.

April 2002 29 M e d Works Media Academic Supplement activity of (+)-(1S, 2 R) - t r a n y l c y p r omine pre d o m i n a t e s p a r e n t ’s therapeutic activity,1 3 but the stereoselectivity of in the therapeutic activity of the racemate. this activity is unknown. The mean plasma S : R enantiomer concentration ratio Antidepressants for venlafaxine in humans is 1.34±0.26, which is not Trimipramine is a tricyclic with a single significantly diff e rent from 1.00.14 This suggests that the chiral center, marketed as the racemate. The (-)-stere o i s o m e r disposition of venlafaxine enantiomers in humans is not is the eutomer at relevant receptors for monoamine markedly stereoselective, hence clinical pharm a c o k i - reuptake inhibitory activity, whereas its antipode is the netic studies using total drug concentration are likely to d i s t o m e r.6 The metabolism of trimipramine is stere o s e - be adequate. However, when venlafaxine is co-adminis- lective: (-)-trimipramine is pre f e r entially metabolized t e r ed with a CYP 2D6 inhibitor, the S : R d e c r eases by by the cytochrome P450 (CYP) isozyme CYP C19, about 20%,1 5 showing that at least one route of metabo- while (+)-trimipramine is pre f e r entially metabolized by lism can be enantioselective in some circumstances. In CYP 2D6. In addition, (+)-trimipramine may be con- addition, subjects who are deficient in CYP 2D6 v e r ted to an uncharacterized metabolite by CYP (described as poor metabolizers) have lower ratios of O- 3 A 4 / 5 . 7 Genetic polymorphism in CYP 2D6 and CYP desmethyl-venlafaxine to venlafaxine in plasma than 2C19, and the wide interindividual variability in CYP other genotypes.1 6 Taken together, these data imply that 3A4 activity, suggest that stereoselective disposition poor metabolizers of CYP 2D6 may have re l a t i v e l y contributes to the striking diff e rences among patients in higher plasma concentrations of (S)-venlafaxine and plasma drug concentrations. lower concentrations of (S)-O-desmethyl venlafaxine c o m p a r ed with efficient metabolizers. Newer Generation Antidepressants The clinical consequences of this diff e r ence re m a i n Bupropion u n c l e a r, but if O-desmethyl venlafaxine enantiomers dis- B u p r opion has a single chiral center and is adminis- play similar antidepressant activity, then non-chiral t e red clinically as the racemate. There appears to be no analysis of this metabolite and the parent will be ade- major diff e rence in the antidepressant activity of bupro- quate for determining concentration-effect re l a t i o n s h i p s , pion enantiomers in animal models of depre s s i o n . 8 independent of CYP 2D6 phenotype, since antidepressant H o w e v e r, metabolism of bupropion introduces an addi- activity is related to the sum of these two species.1 3 I n tional chiral center in its three major metabolites. other words, venlafaxine is probably not a candidate for H y d ro x y - b u p r opion is comparable in potency to bupro- separate isomer development. pion, while the second and third metabolites, thre o h y d ro - b u p r opion and ery t h r o h y d r o - b u p r opion, are about one Reboxetine tenth to one half the potency of the parent compound.9 Reboxetine is a norepinephrine selective re u p t a k e S t e r eoselective plasma concentration of the potent inhibitor with two chiral centers, and is marketed in metabolite has been re p o r ted, with the (-)-enantiomer E u r ope as the racemate of the (+)-(S , S )- and (-)-(R , R ) - being 24-fold greater than its antipode.10 enantiomers. In vitro and in vivo re c e p t o r-binding mod- At present, there are no re p o r ts on the pharm a c o k i- els suggest that the S , S -enantiomer is the more potent netics of the parent enantiomers or the antidepre s s a n t n o r epinephrine ,1 7 although its plasma activity of the metabolite enantiomers. Stere o s e l e c t i v e concentrations are about 2-fold lower following either disposition of the parent compound may be unimport a n t intravenous or oral administration of the racemate.1 8 if the enantiomers have equal therapeutic activity. Equal This is evidently not the result of stereoselective metab- activity also implies that measurement of the bupro p i o n olism, since both enantiomers are oxidized to appro x i - enantiomers would offer little advantage over measure- mately the same degree by CYP 3A4 in in vitro ments of total bupropion for purposes of therapeutic s t u d i e s . 1 9 , 2 0 This is supported by the fact that the enan- d r ug monitoring. The relationship between bupro p i o n tiomers show similar elimination half-lives, re g a r d l e s s plasma concentration and its antidepressant eff e c t s of the route of administration.1 8 remains contro v e r s i a l . The diff e rence between the two enantiomers in plasma concentrations is probably due to greater renal clearance Venlafaxine of (S , S) - re b o x e t i n e . 1 8 , 2 1 The estimated volume of distribu- Venlafaxine is a dual serotonin and norepinephrine re u p- tion for reboxetine enantiomers following an intravenous take inhibitor with a single chiral center. Like bupropion, it dose is approximately 2.4-fold diff e rent. This diff e re n c e is marketed as a racemic mixture. In vitro re c e p t o r- b i n d i n g suggests that the enantioselective disposition of re b o x e- studies suggest that both enantiomers have essentially simi- tine may result from enantioselective tissue binding or lar pharmacologic activity. Venlafaxine is metabolized to two distribution. Reboxetine may be an example of a racemic major metabolites, O-desmethyl-venlafaxine and N- d rug with one clearly active enantiomer, where accurate desmethyl-venlafaxine, by CYP 2D6 and CYP 3A4, re s p e c- definition of the dose-effect relationship has been t i v e l y.1 1 , 1 2 O-desmethyl-venlafaxine contributes to its obscured by enantioselective disposition.

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Selective Reuptake Inhibitors nificant prolongation of cardiac repolarization, reflected by Fluoxetine an increased corrected QT interval (QTc). For this re a s o n , Fluoxetine is a serotonin selective reuptake inhibitor clinical studies were halted, illustrating the potential gap (SSRI) with a single chiral center. The two enantiomers in between theoretical benefits and actual clinical outcomes in the racemic mixture have similar potency as re u p t a k e enantiomer science. In contrast to the rationale for develop- i n h i b i t o r s , 2 2 but the enantiomers of one of its metabolites ing pure (R)-fluoxetine, a pure (S)-fluoxetine form u l a t i o n d i f fer considerably, with (S) - n o r fluoxetine being 5 to 10 has been considered as a treatment for migraine because it times more potent than (R) - n o rfluoxetine (Table 2).2 2 - 2 5 I n may offer a longer duration of action than equivalent doses v i t ro studies suggest that fluoxetine is converted to norf l u o x- of the racemate or (R) - f l u o x e t i n e . 2 9 etine primarily by CYP 2D6, CYP 2C9, and CYP 3A4. Clearance estimates for both enantiomers are similar for Citalopram CYP 2D6 and CYP 3A4; CYP 2C9, however, is more selec- Like fluoxetine, citalopram is an SSRI with a single tive for the R-enantiomer than for the S- e n a n t i o m e r.2 6 chiral center, marketed as a racemic mixture. The (+)-S- While CYP 2D6 metabolizes the parent compound enantiomer of citalopram (known as escitalopram) and its enantiomers at similar rates, clinical studies confirm major metabolite, N-, are 167 and that it acts on only one of the metabolite enantiomers, 6.5 times more potent, re s p e c t i v e l y, than their antipodes (S) - n o r f l u o x e t i n e .2 7 T h e re f o re, in CYP 2D6-deficient sub- in the in vitro inhibition of serotonin reuptake (Table 2).2 4 jects, the elimination half-lives of (R)- and (S) - n o rf l u o x e t i n e CYP 3A4, CYP 2C19, and CYP 2D6 are thought to be a re 6.9 and 17.4 days, re s p e c t i v e l y, whereas the half-lives of involved in the demethylation of citalopram, all with these two enantiomers are similar and shorter in extensive higher rates for the more active S- e n a n t i o m e r. 3 0 metabolizers (5.5 days). Elimination of the parent compound Escitalopram and (S)-desmethylcitalopram are weak or enantiomers also varies between poor and extensive CYP negligible inhibitors of human CYP 1A2, CYP 2E1, CYP 2D6 metabolizers. Finally, the parent compound and the 2C9, CYP 2C19, CYP 2D6, and CYP 3A4.3 1 The second- metabolite are competitive inhibitors of CYP 2D6, with the a ry metabolite, (S)-, is also a weak S-enantiomers of each producing the greatest eff e c t . 2 5 I n inhibitor of CYP 1A2, CYP 2D6, CYP 2E1, and CYP s h o rt, CYP 2D6 participates in the metabolism of fluoxetine, 3A4. Thus, escitalopram is unlikely to cause clinically and in the absence of this isozyme, fluoxetine metabolism important pharmacokinetic interactions. can be enantiomer- s e l e c t i v e . The in vitro data on escitalopram’s greater pharm a c o l o g i c The diff e rences between enantiomers suggested that flu- activity than (R)-citalopram are supported by the results fro m oxetine might be a candidate for drug development as a clinical studies in normal volunteers and patients treated with p u re R- i s o m e r.2 8 The rationale was that (R)-fluoxetine and (R , S)-citalopram, in which the concentration of escitalopram (R) - n o rfluoxetine would cause less inhibition of CYP 2D6 was, on average, 50% lower than its antipode.3 2 - 3 4 Thus, pure activity than the racemate, and that the excessively long escitalopram may offer greater serotonin reuptake inhibition half-life of (S) - n o rfluoxetine in poor CYP 2D6 metabolizers at lower doses than the racemate does. would be avoided. These factors could reduce the pro p e n- Levels of the more potent serotonin reuptake inhibitor, sity for clinically significant dru g - d rug interactions com- escitalopram, were lower than those of the (R) - c i t a l o p r a m . 3 2 p a r ed to the currently marketed racemate. Because Rochat and colleagues demonstrated, via reverse-phase liq- (R)-fluoxetine is less potent than its antipode, the dose uid chro m a t o g r a p h y, that escitalopram plasma levels were needed to provide serotonin reuptake inhibition comparable only about one third of the plasma levels achieved with to that of racemic fluoxetine would be expected to be more (R , S) - c i t a l o p r a m . 3 2 than just half of the racemate dose. In a steady-state pharmacokinetic study, Sidhu and col- U n f o rt u n a t e l y, in Phase II studies of (R)-fluoxetine, the l e a g u e s 3 3 found escitalopram and its metabolites underw e n t highest dose studied was found to cause a statistically sig- a more rapid elimination than their antipodes. Serum esci-

TABLE 2. CHIRALITY AND PHARMACOLOGIC EFFECTS OF SSRIs2 2 , 2 4 , 2 5

(S) Inhibitory (R) Inhibitory D r u g constant, 5-HT (nM)* constant, 5-HT (nM)* S/R Activity Ratio†

Fluoxetine 22 35 1.6 Norfluoxetine 14 309 22.07 Citalopram 1.5 250 166.67 Desmethylcitalopram 10 65 6.5

* Inhibitory constant for inhibition of the synaptosomal uptake of 5-HT as either Ki (nM) for fluoxetine or IC5 0 (nM) for citalopram. Lower numbers indicate higher potency. † Determined as the ratio of the reciprocal of the inhibitory constant for the S-isomer divided by that for the R- i s o m e r. SSRIs=selective serotonin reuptake inhibitors; 5-HT=serotonin. D e Vane CL, Boulton DW. C N S Spectrums. Vol 7, No 4 (suppl 1). 2002.

April 2002 31 M e d Works Media Academic Supplement levels throughout the steady-state dosing interv a l stereoselectivity of their disposition in the mother and the w e re 37%±6% of citalopram concentrations. Steady-state fetus or newborn. The effects of various disease states, levels of (S)-desmethylcitalopram and (S) - d i d e s m e t h y l c i- p r e g n a n c y, age, and gender on the stereoselective phar- talopram were 36% to 48% and 24% to 39%, re s p e c t i v e l y, macokinetics and pharmacodynamics of psychoactive of their racemic concentrations.3 3 d r ugs are also underre s e a r ched areas in most cases. In a clinical study of the effects of aging on citalopram Adding to the complexities of the disposition of a chiral s t e reoselective pharmacokinetics, the plasma concentration psychoactive drug are a host of polymorphisms that give ratio of the enantiomers for citalopram and desmethylcitalo- rise to considerable interindividual variability in the dis- pram in elderly subjects was higher than those in younger position of and response to a drug’s stereoisomers. patients, perhaps reflecting age-related reductions in dru g - With recent advances in chiral analysis and a heightened metabolizing activities (eg, CYP 2C19).3 5 In another study, a w a r eness of the potential for unnecessary toxicity with the (R , S )-citalopram and the (R , S ) - d e s m e t h y l c i t a l o p r a m racemic drugs, some products in current clinical use may be plasma concentration ratios both increased with citalopram replaced by pure eutomer formulations. The advantages of dose, suggesting that their enantioselective disposition is single-enantiomer products include: concentration-dependent and that (R)-citalopram may be • Less complex and more selective inhibiting escitalopram.34 p h a rmacological pro f i l e • Potential for an improved therapeutic index CONCLUSION • Less complex pharmacokinetic pro f i l e Many widely prescribed antidepressants are curre n t l y • Reduced potential for complex drug interactions marketed as racemic mixtures (Table 1). The potential • Less complex relationships between plasma disadvantages of racemic mixtures include the possibility concentration and eff e c t that one of the enantiomers may not participate substan- Racemic citalopram is a pertinent example. The curre n t tially in the therapeutic effects of the administered dru g , f o rmulation is efficacious in the treatment of depression as yet contribute to either adverse events or drug interac- well as panic and obsessive-compulsive disorders. However, tions. As the elimination half-lives of enantiomers may escitalopram is approximately twice as potent as racemic differ, a longer half-life of a less-desirable enantiomer is a citalopram as an inhibitor of serotonin reuptake. Use of esc- f u r ther barrier to developing optimal dosage re c o m m e n - italopram should permit lower doses and an improved thera- dations. The presence of less-active enantiomers also peutic index as well as an improved safety profile with no complicates pharmacokinetic studies on drug disposition i n c rease in drug interaction liability. Clinical trial data sup- and studies relating dose or concentration to clinical p o rt these advantages.3 7 Characterization of the fate of chiral e f fects. These considerations have driven the tre n d p s y c h o t rop ic agents and a greater knowledge of the factors toward developing pure eutomer formulations. that influence their stereospecific disposition and actions Many re g u l a t o ry authorities now re q u i re complete char- will provide a rational basis for their expanded use in vari- acterization of the stereospecific disposition of chiral ous patient populations. C N S d ru g s , 3 6 and it seems appropriate to apply this re q u i re m e n t to chiral drugs already in common use as racemates. P h a rmacokinetic studies based on non-stereoselective data a re often inadequate to describe the fate of chiral dru g s a d m i n i s t e r ed as racemic mixtures. Stereoselectivity is potentially involved at every stage in the disposition of a chiral drug and its neglect can easily lead to misinterpre t a- tion of pharmacokinetic and pharmacodynamic data. In addition, it is now clear that the concept of active and completely inactive stereoisomers of a chiral drug is an oversimplification. The distomer can, in fact, have a multi- tude of effects ranging from antagonism of the eutomer to o v e rt toxicity, or even a beneficial effect that may favor the use of the racemate. Clearly, each drug needs to be consid- e red individually with re g a rd to its use as a single stere o i s o- mer formulation; it is not simply a matter of using a pure eutomer formulation at half the dose of the racemate. Other unexamined aspects of stereoselectivity in dru g metabolism may be therapeutically important. For exam- ple, few studies have examined the placental transfer or b reast milk excretion of psychoactive drugs administere d as racemates, and virtually none have considered the

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2 0 . Wienkers LC, Allievi C, Hauer MJ, Wynalda MA. Cytochrome P450-mediated REFERENCES metabolism of the individual enantiomers of the antidepressant agent re b o x e- 1 . Boulton DW, DeVane CL. Development and application of a chiral high tine in human liver microsomes. D rug Metab Dispos. 1 9 9 9 ; 2 7 : 1 3 3 4 - 1 3 4 0 . p r e s s u re liquid chromatography assay for pharmacokinetic studies of 2 1 . E d w a rds DM, Pellizzoni C, Breuel HP, et al. Pharmacokinetics of re b o x e- methadone. C h i r a l i t y. 2000;12:681-687. tine in healthy volunteers. Single oral doses, linearity and plasma pro t e i n 2 . Boulton DW, Arnaud P, DeVane CL. Pharmacokinetics and pharm a c o d y- binding. B i o p h a rm Drug Dispos. 1 9 9 5 ; 1 6 : 4 4 3 - 4 6 0 . namics of methadone enantiomers in normal female volunteers following a 2 2 . Wong DT, Threlkeld PG, Robertson DW. Affinities of fluoxetine, its enan- single oral dose of racemate. 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