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Role of Stereoselective Assays in Bioequivalence Studies of Racemic Drugs: Have We Reached a

Consensus?
Nuggehally R Srinivas
J Clin Pharmacol 2004 44: 115
DOI: 10.1177/0091270003262098

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ARTICLE
STEREOSELECTIVE
SRINIVAS
10.1177/0091270003262098
DRUG DEVELOPMENT ASSAYS OF RACEMIC DRUGS
Role of Stereoselective Assays in
Bioequivalence Studies of Racemic Drugs:
Have We Reached a Consensus?
Nuggehally R. Srinivas, PhD, FCP
The existence of stereoselectivity in metabolism and drug
disposition, coupled with the existence of genetic poly-
morphisms and modulation of enantiomeric kinetics via spe-
cial delivery systems, provides some compulsion to assess
bioequivalence using stereoselective data. However, exami-
nation of the literature suggests that nonstereoselective data
I n the past two decades, numerous analytical proce-
dures to determine the individual chiral compo-
nents of a racemic drug have been published. At the
present time, the impetus for explosive growth in the
stereoselective separation and quantification of drug
racemates can be attributed to (1) the commercial avail-
ability of excellent chiral derivatization reagents to
derivatize the functional handles on the enantiomeric
substrates to form diastereomeric complexes for indi-
rect separation1-3 and (2) the commercial availability of
various chiral stationary phases with a thorough
knowledge of chiral separation mechanisms for direct
separation.4-8 The availability of other chromato-
graphic-related procedures such as thin-layer chroma-
tography,9 super-critical fluid chromatography,10-13
subcritical fluid chromatography,13 and capillary elec-
trophoresis14,15 have further broadened the horizon for
the resolution and quantification of chiral entities.
The development of sound stereoselective assays
has paved the way for delineating the pharma-
cokinetics of several important drug racemates. How-
ever, in the past, characterizing the pharmacokinetics
From Drug Development, Dr. Reddy’s Research Laboratories—Discovery
Research, Miyapur, Hyderabad, India. Submitted for publication Decem-
ber 29, 2002; revised version accepted December 21, 2003; . Address
for reprints: N. R. Srinivas, Vice President, Drug Development, Dr. Reddy’s
Research Laboratories—Discovery Research, Bollaram Road, Miyapur,
Hyderabad, India.
DOI: 10.1177/0091270003262098
J Clin Pharmacol 2004;44:115-119
Downloaded from jcp.sagepub.com by ioana m on November 24, 2010
DRUG DEVELOPMENT
are commonly used for the bioequivalence assessment of
drug racemates.
Keywords: Stereoselectivity; chiral; racemate; pharma-
cokinetics; bioequivalence
Journal of Clinical Pharmacology, 2004;44:115-119
©2004 the American College of Clinical Pharmacology
of the individual enantiomers was not adequately per-
formed since stereoselective assays were not originally
available when those drug racemates were developed
and subsequently registered for human consumption.
Furthermore, now it is widely recognized that chirality
in a drug molecule cannot be discounted during the
drug development process, which encompasses the
following: understanding of drug action; characteriza-
tion of the pharmacologic, toxicologic, pharma-
cokinetic, and pharmacodynamic profiles; and safety,
tolerability, and efficacy assessment.16-20
Nowadays, the employment of stereoselective as-
says for delineating the absorption, distribution, me-
tabolism, and excretion profiles of the individual an-
tipodes of drug racemates in both clinical and
nonclinical studies has become a common practice. Al-
though stereoselective assays have gained momentum
and popularity in the pharmacokinetic/pharma-
codynamic arena, using stereoselective assays in the
bioequivalence establishment of racemic drugs is sur-
rounded by a cloud of controversy, with both the pro-
ponents and opponents of this issue involved in an on-
going debate.21-25 The proponents believe that if the
pharmacological activity or the toxicity of the racemate
is due to the predominant (or entire) contribution of
one enantiomer, bioequivalence testing should con-
sider the active form of the enantiomer rather than the
total (active + less active or inactive). On the other
hand, the opponents argue that employment of
stereoselective assays will only add to the develop-
115
 SRINIVAS
mental cost, with no clear advantages, and nonstereo-
selective (total) measurement should be adequate for
establishing bioequivalence. They also believe that
measurement of the individual antipodes will not
change the bioequivalence outcome because the
racemates in both the test and reference products have
a fixed ratio (1:1) of the two enantiomers. However, de-
spite such varied viewpoints, it appears that there is a
general consensus for not employing stereoselective
assay(s) in showing bioequivalence for such racemic
drugs that have individual antipodes that are qualita-
tively and quantitatively similar in their pharma-
cological outcome and exhibit no differences in their
respective pharmacokinetic/disposition profiles.
The intent of this article is to discuss the relevance
and utility of stereoselective versus nonstereoselective
assays in bioequivalence assessment from the perspec-
tives of stereoselective metabolism/disposition,
stereoselective pharmacogenetics, and modulation of
stereoselective pharmacokinetics via specialized de-
livery systems or a new fixed-combination dose of two
drug enantiomers.
A recently published commentary examines,
proposes, and recommends a pharmacokinetic/
pharmacodynamic strategy for the employment of
stereoselective assays in establishing bioequivalence
of racemic drugs subjected to presystemic metabo-
lism.26 According to the proposal, racemic drugs are
classified into three groups: (1) racemic drugs exhibit-
ing negligible or nonstereoselective presystemic (i.e.,
first-pass) metabolism, (2) racemic drugs exhibiting
significant presystemic metabolism of the less pharma-
cologically active enantiomer (distomer) compared to
the more active enantiomer (eutomer), and (3) racemic
drugs exhibiting significant presystemic metabolism of
the eutomer compared to its distomer. On the basis of
the activity and side effect profiles of the racemic drug
under consideration, it is important to establish a priori
the difference in the area under the curve that will con-
stitute a significance in the drug action of the two enan-
tiomers of the racemic drug. In addition to knowing the
information on the stereoselective presystemic metab-
olism of the racemic drug, it is also important to gather
data on the saturability of the stereoselective pre-
systemic metabolism, the involvement of other active/
passive elimination process(es) (e.g., renal and biliary)
and the saturability of such process(es), and the effects
of protein binding and changes in the free-fraction
equilibrium on the overall enantiomeric systemic dis-
tribution and clearance. Such additional information
may be useful in understanding the pharmacokinetic
behavior of the racemic drug at different dosage
116 • J Clin Pharmacol 2004;44:115-119
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strengths (within the therapeutic range) and varied in-
put rates (tablet vs. capsule vs. solution). On a similar
ground to Karim’s report,26 Mehavar and Jamali27 have
examined the issue of stereoselective versus
nonstereoselective assays for bioequivalence assess-
ment using original case studies with additional sup-
port from simulation experiments. On the basis of the
report, they recommend using the bioequivalence of
individual enantiomers for drug racemates that exhibit
nonlinear pharmacokinetics and for drug racemates
that exhibit pronounced enantioselective differences
in the pharmacokinetic profiles despite having linear
pharmacokinetics. In addition, the authors suggest us-
ing this approach for racemic drugs that undergo chiral
inversion. They also recommend the use of the total
drug approach (nonstereoselective assay) for assess-
ing the bioequivalence of racemic drugs with linear
pharmacokinetics and minimal to moderate stereose-
lectivity in their kinetic parameters.27
Another perspective that needs to be factored in this
debate is obviously the role of stereoselective pharma-
cogenetics in the disposition of racemic drugs.28-35 If a
stereoselective assay is not employed, it is quite likely
that one may not observe the true disposition differ-
ences of the drug in the patient population predisposed
to genetic polymorphism. For example, recently,
Tanaka et al29 described the stereoselective pharma-
cogenetics of pantoprazole in extensive and poor
metabolizers of S-mephenytoin. Clearly, having a
stereoselective assay paved the way to ascertaining that
the metabolism of (+)-pantoprazole was impaired to a
greater extent than (–)-pantoprazole in the poor
metabolizers of CYP2C19. Another example, with
added complexity, relates to the work of Foglia et al,36
who have shown that stereoselective metabolism of
citalopram and its metabolite desmethylcitalopram
was more pronounced in the elderly as compared to
younger subjects due to age-related changes in
CYP2C19 activities. The question is whether mere
racemic (total drug) data, without comparative
stereoselective pharmacokinetic data, justify the
bioequivalence assessment of drugs that are known to
exhibit genetic polymorphism. More thought has to be
given for designing bioequivalence studies to drugs in
this area, paying attention to the role of active metabo-
lite(s) in addition to stereoselective pharmacogenetic
components responsible for the disposition of the drug.
Given the mundane and unattractive nature of
bioequivalence testing, complacency should not pre-
vail in taking an easy path. For example, it may not be
simple enough to homogenize the patient population
and only perform the bioequivalence assessment in
 STEREOSELECTIVE ASSAYS OF RACEMIC DRUGS
one of the phenotypes (poor metabolizers or extensive
metabolizers) using a nonstereoselective assay.
Yet another dilemma in the ongoing debate is artic-
ulated by a recent publication of Modi et al.37 In this
work, the authors have demonstrated that oral deliv-
ery of dl-threo-methylphenidate through an OROS®
system can modulate the stereoselective metabolism
of methylphenidate such that less of l-threo-
methylphenidate, the inactive enantiomer, is
systemically delivered as compared to the regular
immediate-release or sustained-release formulations of
dl-threo-methylphenidate.38,39 Therefore, such formu-
lations can enhance the therapeutic index of dl-threo-
methylphenidate by modulating its presystemic me-
tabolism in the local gastrointestinal environment. An-
other study, supporting the influence of the input rate
on presystemic stereoselective metabolism, involves
different extended-release prototype formulations of
metoprolol.40 On the basis of evaluating slow-release,
moderate-release, and fast-release extended formula-
tions in relation to an oral solution, the authors have re-
ported that both in the absorptive and terminal phases,
the fast-input formulations (solution and fast extended
release) show profound stereoselective differences as
compared to the other slower input extended-release
formulations.40 This observation of input-based
stereoselective pharmacokinetics was confirmed for
both metoprolol and its metabolites.40 In this context, if
a special delivery device or extended-release system is
being pursued, it is important to assess bioequivalence
by emphasizing stereoselective analysis. A mere routine
analysis by a nonstereoselective assay may not necessar-
ily pick the subtle yet important stereoselective
pharmacokinetic differences between such devices
during their gastrointestinal transit while releasing the
drug from the matrix. To further emphasis this point,
Aberg et al41 have confirmed the bioequivalence of the
new fixed combination of metoprolol and felodipine
with the individual components and suggest the clini-
cal interchangeability of the new fixed combination
with the readily available free combination of the two
agents. However, most important, the authors have ex-
tended their evaluation to the stereoselective aspects,
although the interchangeability of the two formula-
tions was based on the racemate data. By employing
appropriate enantioselective methods for felodipine
and metoprolol, the authors concluded that the mean
plasma S:R enantiomer ratios were identical for the
two agents regardless of the treatment.41 The work of
Aberg et al reemphasizes the need for a cautious out-
look when dealing with the bioequivalence of drug
DRUG DEVELOPMENT
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racemates when formulated as a fixed-combination
dose. Therefore, the inclusion of a stereoselective in-
vestigation clearly addressed what otherwise would
have been a nagging question regarding the contribu-
tion of individual enantiomers of the two agents and/or
the relevance of the racemate approach to conclude
bioequivalence.
Because there is no regulatory precedence or thera-
peutic relevance to address stereochemical aspects in
bioequivalence studies at the present time, there are
only a few examples in the literature whereby the in-
vestigators have employed stereoselective assays in the
bioequivalence testing of racemic drugs.42-50 The view-
points expressed by Karim26 and Mehavar and Jamali27
should be explored when making the decision to use
nonstereoselective versus stereoselective assays. In ad-
dition, the role of stereoselective pharmacogenetics,
active metabolite(s) formation, and modulation of
stereoselective pharmacokinetics/metabolism using
special delivery system(s) and/or a fixed-dose combi-
nation need to be considered when making the
decision.
Although viewpoints to reach consensus in the de-
bate of stereoselective versus nonstereoselective data
for bioequivalence assessment have been made in the
past, it is not clear from a regulatory point of view what
the stand is toward the bioequivalence assessment of a
drug racemate. However, it appears that nonstereo-
selective data are adequate for bioequivalence assess-
ment and approval. Because many drug racemates will
become generic in the coming years, the practice of as-
sessing bioequivalence by applying nonstereoselective
data of the generic product with the innovator’s prod-
uct may not be prudent for all the molecules. Perhaps
the requirement of supplying stereoselective data in a
certain percentage of subjects may help in understand-
ing the qualitative performance of the product in rela-
tion to the stereoselective disposition of the drug. This,
in turn, ensures a certain level of diligence in informa-
tion gathering from a public health perspective when a
generic drug racemate product is introduced.
The availability of a plethora of stereoselective as-
say procedures should enhance the opportunity for
the bioequivalence assessment of racemic drugs us-
ing individual enantiomeric data. However, the mere
availability of a plethora of stereoselective methods
should not tilt the balance toward the routine evalua-
tion of racemates’ bioequivalence with the individual
enantiomeric data. Needless to say, because good sci-
ence is very often achieved by having a well-planned
and controlled experimental design, it is important to
117
 SRINIVAS
delineate, a priori, the use of nonstereoselective versus
stereoselective assays using facts, common sense, and a
rational thought process.
REFERENCES
1. Srinivas NR, Igwemezie LN: Chiral separation by high performance
liquid chromatography: I. Review on indirect separation of enantio-
mers as diastereomeric derivatives using ultraviolet, fluorescence
and electrochemical detection. Biomed Chromatogr 1992;6:163.
2. Srinivas NR, Shyu WC, Barbhaiya RH: Gas chromatographic deter-
mination of enantiomers as diastereomers following pre-column
derivatization and applications to pharmacokinetic studies: a review.
Biomed Chromatogr 1995;9:1.
3. Sun XX, Sun LZ, Aboul-Enein HY: Chiral derivatization reagents
for drug enantioseparation by high-performance liquid chromatogra-
phy based upon pre-column derivatization and formation of
diastereomers: enantioselectivity and related structure. Biomed
Chromatogr 2001;15(2):116-132.
4. Aboul-Enein HY: Recent applications of polysaccharide-type
chiral stationary phases for the enantioselective analysis of chiral
drugs with one and two stereogenic centers. Biomed Chromatogr
1998;12:116-119.
5. Ward TJ, Francis AB III: Chiral separations using the macrocyclic
antibiotics: a review. J Chromatogr A 2001;906:73-89.
6. Williams ML, Wainer IW: Role of chiral chromatography in thera-
peutic drug monitoring and in clinical and forensic toxicology. Ther
Drug Monitor 2002;24:290-296.
7. Aboul-Enein HY: High-performance liquid chromatographic
enantioseparation of drugs containing multiple chiral centers on
polysaccharide-type chiral stationary phases. J Chromatogr A 2001;
906:185-193.
8. Piras P, Roussel C, Pierrot-Saunders J: Reviewing mobile phases
used on Chiralcel OD through an application of data mining tools to
CHIRBASE database. J Chromatogr A 2001;906:443-458.
9. Aboul-Enein HY, El-Awady MI, Heard CM, Nicholls PJ: Applica-
tion of thin-layer chromatography in enantiomeric chiral analysis: an
overview. Biomed Chromatogr 1999;13:531-537.
10. Johannsen M: Separation of enantiomers of ibuprofen on chiral
stationary phases by packed column supercritical fluid chromatogra-
phy. J Chromatogr A 2001;937:135-138.
11. Svensson LA, Owens PK: Enantioselective supercritical fluid
chromatography using ristocetin A chiral stationary phases. Analyst
2000;125:1037-1039.
12. Hoke SH, Pinkston JD, Bailey RE, Tanguay SL, Eichold TH:
Comparison of packed-column supercritical fluid chromatography-
tandem mass spectrometry for bioanalytical determination of (R)-
and (S)-ketoprofen in human plasma following automated 96-well
solid-phase extraction. Anal Chem 2000;72:4235-4241.
13. Kot A, Sandra P, Venema A: Sub- and supercritical fluid chroma-
tography on packed columns: a versatile tool for the enantioselective
separation of basic and acidic drugs. J Chromatogr Sci 1994;32:439-
448.
14. Andersen S, Halvorsen TG, Pedersen-Bjergaard S, Rasmussen KE:
Liquid-phase microextraction combined with capillary electrophore-
sis, a promising tool for the determination of chiral drugs in biologi-
cal matrices. J Chromatogr A 2002;963:303-312.
118 • J Clin Pharmacol 2004;44:115-119
Downloaded from jcp.sagepub.com by ioana m on November 24, 2010
15. Matsunga H, Haginaka J: Separation of basic drugs enantiomers by
capillary electrophoresis using ovoglycoprotein as a chiral selector:
comparison of chiral resolution ability of ovoglycoprotein and com-
pletely deglycosylated ovoglycoprotein. Electrophoresis 2001;22:
3252-3256.
16. Strong M: FDA policy and regulation of stereoisomers: paradigm
shift and the future of safer, more effective drugs. Food Drug Law J
1999:54:463-487.
17. Ariens EJ, Wuis EW: Bias in pharmacokinetics and clinical phar-
macology. Clin Pharmacol Ther 1987;42:361.
18. Caldwell J: The importance of stereochemistry in drug action and
disposition. J Clin Pharmacol 1992;32:925-929.
19. Nation RL: Chirality in new drug development: clinical
pharmacokinetic considerations. Clin Pharmacokin 1994;27:249-
255.
20. Srinivas NR, Barbhaiya RH, Midha KK: Enantiomeric drug devel-
opment: issues, considerations, and regulatory requirements. Invited
Min-Review. J Pharm Sci 2001;90(9):1205-1215.
21. Jamali F: Stereochemistry and bioequivalence. J Clin Pharmacol
1992;32:930-934.
22. Wechter WJ: From controversy to resolution: bioequivalency of
racemic drugs—a symposium on the dynamics, kinetics, bioequiva-
lency, and analytical aspects of stereochemistry. J Clin Pharmacol
1992;32:915-916.
23. Nerurkar SG, Dighe SV, Williams RL: Bioequivalence of racemic
drugs. J Clin Pharmacol 1992;32:935-943.
24. Hooper WD, Dickinson RG, Gal J: Enantioselective versus non-
enantioselective assays in comparative bioavailability studies with
racemic drugs. Biopharm Drug Disp 1992;13:383-387.
25. Jamali F: Enantioselective versus non-enantioselective assays in
comparative bioavailability studies for racemic drugs. Biopharm
Drug Disp 1992;13:385.
26. Karim A: Enantioselective assays in comparative bioavailability
studies of racemic drug formulations: nice to know or need to know. J
Clin Pharmacol 1996;36:490-499.
27. Mehvar R, Jamali F: Bioequivalence of chiral drugs: stereospecific
versus non-stereospecific methods. Clin Pharmacokin 1997;33:
122-141.
28. Niwa T, Shiraga T, Mitani Y, Terakawa M, Tokuma Y, Kagayama A:
Stereoselective metabolism of cibenzoline, an antiarrhythmic drug,
by human and rat liver microsomes: possible involvement of CYP2D
and CYP3A. Drug Metab Dispos 2000;28:1128-1134.
29. Tanaka M, Ohkubo T, Otani K, Suzuki A, Kaneko S, Sugawara K,
et al: Stereoselective pharmacokinetics of pantoprazole, a proton
pump inhibitor, in extensive and poor metabolizers of S-
mephenytoin. Clin Pharmacol Ther 2001;69:108.
30. Labbe L, Abolfathi Z, Robitaille NM, St. Maurice F, Gilbert M,
Turgeon J: Stereoselective disposition of the antiarrhythmic agent
mexiletine during the concomitant administration of caffeine. Ther
Drug Monitor 1999;21:191.
31. Andersson T, Hassan-Alin M, Hasselgren G, Rohss K, Weidolf L:
Pharmacokinetic studies with esomeprazole, the (S)-isomer of
omeprazole. Clin Pharmacokin 2001;40:411-426.
32. Haritos VS, Ghabiral H, Ahokas JT, Ching MS: Role of cytochrome
P450 2D6 (CYP2D6) in the stereospecific metabolism of E- and Z-
doxepin. Pharmacogenetics 2000;10:591.
33. Rasmussen BB, Brosen K: Is therapeutic drug monitoring a case
for optimizing clinical outcome and avoiding interactions of the se-
 STEREOSELECTIVE ASSAYS OF RACEMIC DRUGS
lective serotonin reuptake inhibitors? Ther Drug Monitor 2000;
22:143.
34. Katsuki H, Hamada A, Nakamura C, Arimori K, Nakano M: Role of
CYP3A4 and CYP2C19 in the stereoselective metabolism of
lansoprazole by human liver microsomes. Eur J Clin Pharmacol 2001;
57:709-715.
35. Mamiya K, Leiri I, Shimamoto J, Yukawa E, Imai J, Ninomiya H,
et al: The effects of genetic polymorphisms of CYP2C9 and CYP2C19
on phenytoin metabolism in Japanese adult patients with epilepsy:
studies in stereoselective hydroxylation and population pharma-
cokinetics. Epilepsia 1998;39:1317.
36. Foglia JP, Pollock BG, Kirshner MA, Rosen J, Sweet R, Mulsant B:
Plasma levels of citalopram enantiomers and metabolites in elderly
patients. Pyschopharmacol Bull 1997;33:109.
37. Modi NB, Wang B, Noveck RJ, Gupta SK: Dose proportional and
stereospecific pharmacokinetics of methylphenidate delivered using
an osmotic controlled release oral delivery system. J Clin Pharmacol
2000;40:1141.
38. Srinivas NR, Hubbard JW, Korchinski ED, Midha KK:
Enantioselective pharmacokinetics of dl-threo-methylphenidate in
humans. Pharm Res 1993;10:14.
39. Hubbard JW, Srinivas NR, Quinn D, Midha KK: Enantioselective
aspects of the disposition of dl-threo-methylphenidate after the ad-
ministration of a sustained-release formulation to children with at-
tention deficit-hyperactivity disorder. J Pharm Sci 1989;78:944.
40. Mistry B, Leslie JL, Eddington ND: Influence of input rate on the
stereospecific and nonstereospecific first pass metabolism and
pharmacokinetics of metoprolol extended release formulations.
Chirality 2002;14:297-304.
41. Aberg J, Abrahamsson B, Grind M, Nyberg G, Olofsson B:
Bioequivalence, pharmacokinetic and pharmacodynamic response
to combined extended release formulations of felodipine and
metoprolol in healthy volunteers. Eur J Clin Pharmacol 1997;52:
471-477.
DRUG DEVELOPMENT
Downloaded from jcp.sagepub.com by ioana m on November 24, 2010
42. Jamali F, Collins DS, Berry BW, Molder S, Cheung R, McColl K,
et al: Comparative bioavailability of two flurbiprofen products:
stereospecific versus conventional approach. Biopharm Drug Disp
1991;12:435-445.
43. Walker SE, Hardy BG: Alterations in apparent bioequivalency of
ibuprofen based on isomer analysis. J Clin Pharmacol 1992;32:957.
44. Cox SR, Brown MA, Squires DJ, Murrill EA, Lednicer D, Knuth
DW: Comparative human study of ibuprofen enantiomer plasma con-
centrations produced by two commercially available ibuprofen tab-
lets. Biopharm Drug Disp 1988;9:539-549.
45. Srinivas NR, Barr WH, Shyu WC, Mohandoss E, Chow S, Staggers
J, et al: Bioequivalence of two tablet formulations of nadolol using
single and multiple dose data: assessment using stereospecific and
nonstereospecific assays. J Pharm Sci 1996;85:299.
46. Midha KK, Hubbard JW, Rawson MJ, Schwede R: The roles of
stereochemistry and partial areas in a parallel design study to assess
the bioequivalence of two formulations of hydroxychloroquine: a
drug with a very long half life. Eur J Pharm Sci 1996;4:283-292.
47. Midha KK, Hubbard JW, Rawson MJ, Schwede R: The impact of
stereoisomerism in a bioequivalence study on two formulations of
doxepin. Eur J Pharm Sci 1996;4:133-138.
48. Boni JR, Korth-Bradley JM, Richards LS, Chiang ST, Hicks DR,
Benet LZ: Chiral bioequivalence: effect of absorption rate on racemic
etodolac. Clin Pharmacokin 2000;39:459.
49. Bui TH, Fernandez C, Vu K, Nguyen KH, Thuillier A, Farinotti R,
et al: Stereospecific versus nonstereospecific assessments for the
bioequivalence of two formulations of racemic chlorpheniramine.
Chirality 2000;12:599-605.
50. Deprez D, Chassard D, Baille P, Mignot A, Ung HL, Puozzo C:
Which bioequivalence study for a racemic drug? Application to
milnacipran. Eur J Drug Metab Pharmacokin 2000;23:166.
119