Clinical pharmacokinetics of nadolol: A systematic review.

WHAT IS KNOWN AND OBJECTIVE: Nadolol is a non-selective beta-adrenergic antagonist that is used for the treatment of hypertension and angina. The primary route for its administration is oral. It is given once daily as it has a longer half-life (t½). The purpose of conducting this systematic review is to provide a comprehensive view of all the available pharmacokinetic (PK) data on nadolol in humans. This review aimed to systematically collate and analyze publish data on the clinical PK of nadolol in humans and this can be beneficial for the clinicians in dosage adjustments. METHODS: Two electronic databases PubMed and Google Scholar were used for conducting a systematic literature search. All the relevant articles containing PK data of nadolol in humans were retrieved. A total of 1275 articles were searched from both databases and after applying eligibility criteria finally, 22 articles were included for conducting the systematic review. RESULTS AND DISCUSSION: The area under the plasma concentration curve (AUC) and maximum plasma concentration (Cmax ) of nadolol increased in a dose-dependent manner. The t½ of nadolol was increased to double (18.2-68.6 h) in the patients with chronic kidney disease while the serum t½ became shorter (3.2-4.3 h) when administered to the children. The bioavailability of nadolol was greatly reduced by the coadministration of green tea. Nadolol can be effectively removed by hemodialysis. It undergoes enterohepatic circulation thus activated charcoal decreased its bioavailability. WHAT IS NEW AND CONCLUSION: Since, there is no previous report of a systematic review on the PK of nadolol, the current review encompasses all the relevant published articles on nadolol in humans. The analysis and understanding of PK parameters (AUC, Cmax , and t½) of nadolol may be helpful in the development and evaluation of PK models.

Urinary Excretion of Nadolol as a Possible In Vivo Probe for Drug Interactions Involving P-Glycoprotein.

Nadolol is a hydrophilic and nonselective ß-adrenoceptor blocker with a bioavailability of 30%, relatively longer half-life, negligible metabolism, and predominant renal excretion. Previous studies have reported that nadolol is a substrate of P-glycoprotein, and the coadministration with itraconazole, a typical P-glycoprotein inhibitor, results in elevated plasma concentrations and cumulative urinary excretion of nadolol. In this study, we assessed whether measurements of urinary-excreted nadolol can be an alternative method of plasma pharmacokinetics for P-glycoprotein-mediated drug interactions in humans. We reanalyzed the pooled data set of plasma concentration and urinary excretion of nadolol from our previous clinical studies in a total of 32 healthy Japanese adults. The area under the plasma concentration-time curve from 0 to infinity (AUC0-∞ ) of nadolol in individual subjects was significantly correlated with the maximum plasma concentration (r = 0.80, P < .01) and the cumulative amount excreted into urine (Ae ) at 4 (r = 0.51, P = .01), 8 (r = 0.63, P < .01), 24 (r = 0.75, P < .01), and 48 (r = 0.77, P < .01) hours. Significant correlations were also observed between the AUC and Ae during the same respective periods. In the drug interactions of nadolol with itraconazole, rifampicin, a well-known P-glycoprotein inducer, or grapefruit juice, there were significant correlations between the differences in AUC0-48 and those in Ae, 0-48 from the controls in individual subjects. These results suggest that the measurements of urinary excretion of nadolol can be employed as a sensitive and reliable alternative to plasma pharmacokinetics for the evaluation of P-glycoprotein-mediated drug interactions.

Role of (-)-epigallocatechin gallate in the pharmacokinetic interaction between nadolol and green tea in healthy volunteers.

PURPOSE: The aim of the present study is to investigate a possible role of a single dose of (-)-epigallocatechin gallate (EGCG), the major catechin in green tea, for the pharmacokinetic interaction between green tea and nadolol in humans. METHODS: In a randomized three-phase crossover study, 13 healthy volunteers received single doses of 30 mg nadolol orally with water (control), or an aqueous solution of EGCG-concentrated green tea extract (GTE) at low or high dose. Plasma concentrations and urinary excretion of nadolol were determined up to 48 h. In addition, blood pressure and pulse rate were monitored. In vitro transport kinetic experiments were performed using human embryonic kidney 293 cells stably expressing organic anion transporting polypeptide (OATP)1A2 to evaluate the inhibitory effect of EGCG on OATP1A2-mediated substrate transport. RESULTS: Single coadministration of low and high dose GTE significantly reduced the plasma concentrations of nadolol. The geometric mean ratios with 90% CI for area under the plasma concentration-time curves from 0 to infinity of nadolol were 0.72 (0.56-0.87) for the low and 0.60 (0.51-0.69) for the high dose. There were no significant differences in Tmax, elimination half-life, and renal clearance between GTE and water phases. No significant changes were observed for blood pressure and pulse rate between phases. EGCG competitively inhibited OATP1A2-mediated uptake of sulphobromophthalein and nadolol with Ki values of 21.6 and 19.4 µM, respectively. CONCLUSIONS: EGCG is suggested to be a key contributor to the interaction of green tea with nadolol. Moreover, even a single coadministration of green tea may significantly affect nadolol pharmacokinetics.

Overview of green tea interaction with cardiovascular drugs.

Sensitive to the massive diffusion of purported metabolic and cardiovascular positive effects of green tea and catechincontaining extracts, many consumers of cardiovascular drugs assume these products as a "natural" and presumably innocuous adjunctive way to increase their overall health. However, green tea may interfere with the oral bioavailability or activity of cardiovascular drugs by various mechanisms, potentially leading to reduced drug efficacy or increased drug toxicity. Available data about interactions between green tea and cardiovascular drugs in humans, updated in this review, are limited so far to warfarin, simvastatin and nadolol, and suggest that the average effects are mild to modest. Nevertheless, in cases of unexpected drug response or intolerance, it is warranted to consider a possible green tea-drug interaction, especially in people who assume large volumes of green tea and/or catechin-enriched products with the conviction that "more-is-better".

Green tea ingestion greatly reduces plasma concentrations of nadolol in healthy subjects.

This study aimed to evaluate the effects of green tea on the pharmacokinetics and pharmacodynamics of the ß-blocker nadolol. Ten healthy volunteers received a single oral dose of 30 mg nadolol with green tea or water after repeated consumption of green tea (700 ml/day) or water for 14 days. Catechin concentrations in green tea and plasma were determined. Green tea markedly decreased the maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC(0-48)) of nadolol by 85.3% and 85.0%, respectively (P < 0.01), without altering renal clearance of nadolol. The effects of nadolol on systolic blood pressure were significantly reduced by green tea. [(3)H]-Nadolol uptake assays in human embryonic kidney 293 cells stably expressing the organic anion-transporting polypeptides OATP1A2 and OATP2B1 revealed that nadolol is a substrate of OATP1A2 (Michaelis constant (K(m)) = 84.3 µmol/l) but not of OATP2B1. Moreover, green tea significantly inhibited OATP1A2-mediated nadolol uptake (half-maximal inhibitory concentration, IC(50) = 1.36%). These results suggest that green tea reduces plasma concentrations of nadolol possibly in part by inhibition of OATP1A2-mediated uptake of nadolol in the intestine.

Effects of green tea extract and (-)-epigallocatechin-3-gallate on pharmacokinetics of nadolol in rats.

Green tea catechins have been shown to affect the activities of drug transporters in vitro, including P-glycoprotein and organic anion transporting polypeptides. However, it remains unclear whether catechins influence the in vivo disposition of substrate drugs for these transporters. In the present study, we investigated effects of green tea extract (GTE) and (-)-epigallocatechin-3-gallate (EGCG) on pharmacokinetics of a non-selective hydrophilic ß-blocker nadolol, which is reported to be a substrate for several drug transporters and is not metabolized by cytochrome P450 enzymes. Male Sprague-Dawley rats received GTE (400 mg/kg), EGCG (150 mg/kg) or saline (control) by oral gavage, 30 min before a single intragastric administration of 10 mg/kg nadolol. Plasma and urinary concentrations of nadolol were determined using high performance liquid chromatography. Pharmacokinetic parameters were estimated by a noncompartmental analysis. Pretreatment with GTE resulted in marked reductions in the maximum concentration (Cmax) and area under the time-plasma concentration curve (AUC) of nadolol by 85% and 74%, respectively, as compared with control. In addition, EGCG alone significantly reduced Cmax and AUC of nadolol. Amounts of nadolol excreted into the urine were decreased by pretreatments with GTE and EGCG, while the terminal half-life of nadolol was not different among groups. These results suggest that the coadministration with green tea catechins, particularly EGCG, causes a significant alteration in the pharmacokinetics of nadolol, possibly through the inhibition of its intestinal absorption mediated by uptake transporters.

Pharmacokinetic and pharmacodynamic interaction of nadolol with itraconazole, rifampicin and grapefruit juice in healthy volunteers.

To evaluate effects of itraconazole, rifampicin and grapefruit juice on pharmacokinetics and pharmacodynamics of a hydrophilic non-selective ß-adrenoceptor blocker nadolol, we conducted an open-label, four-way crossover study in 10 healthy male volunteers. A single oral dose of 30 mg nadolol was administered with water (control), itraconazole (100 mg), or grapefruit juice (300 mL), or after a 6-day pretreatment with rifampicin (450 mg/day). Plasma concentrations and urinary excretions of nadolol were measured over 48 hours after its dosing. Systolic and diastolic blood pressures and pulse rate were periodically recorded after nadolol administration as pharmacodynamic parameters. Itraconazole increased the peak plasma concentration and the area under the plasma concentration-time curve (AUC0-∞ ) of nadolol by 468% and 224% of control, respectively (P < .001). A slight, but not statistically significant, decrease in AUC0-∞ of nadolol was observed in rifampicin and grapefruit juice phases as compared to control. Elimination half-life for nadolol did not differ among the four phases. During itraconazole phase, nadolol reduced pharmacodynamic parameters to a greater extent than the other phases. These results suggest that itraconazole substantially increases the oral availability of nadolol possibly by the inhibition of intestinal P-glycoprotein, whereas grapefruit juice has little effect on nadolol pharmacokinetics.

Effects of itraconazole, dexamethasone and naringin on the pharmacokinetics of nadolol in rats.

The aim of the present study was to clarify the involvement of P-glycoprotein (P-gp) or organic anion transporting polypeptide (Oatp) 1a5 in the pharmacokinetics of nadolol (NDL), a non-metabolized hydrophilic ß-adrenoceptor blocker, in rats. Pretreatment with itraconazole (ICZ, P-gp inhibitor, 50 mg/kg) for 30 min before oral administration of NDL (10 mg/kg) significantly increased the area under the plasma concentration-time curve (AUC0₋∞)of NDL by 1.7-fold compared with control. Intragastric administration of dexamethasone (DEX, 8 mg/kg) for 4 consecutive days increased P-gp level in the intestine and the liver. In line with this, DEX pre-treatment decreased maximum plasma concentration (C(max)) of NDL by 28% of control. To inhibit the intestinal Oatp1a5, naringin (NRG, 0.145 mg/kg) was preadministered orally for 30 min before the oral administrations of NDL or celiprolol (CEL, 10 mg/kg, Oatp1a5 substrate). Although NRG markedly reduced C(max) and AUC0₋∞ of CEL by 60% and 65% of control, respectively, little difference was observed in the plasma concentration of NDL between NRG and control. These results suggest that P-gp is greatly involved in the pharmacokinetics of NDL, while the involvement of Oatp1a5 in the pharmacokinetics of NDL may be less than that of celiprolol in rats.

Estudio comparativo de grupos independientes de pacientes con migraña episódica tratados preventivamente con flunaricina o nadolol / A study to compare independent groups of patients with episodic migraine who were treated preventively with flunarizine or nadolol

Introducción. La flunaricina, con nivel de evidencia A, y el nadolol, con nivel de evidencia C, estarían indicados como tratamiento preventivo de la migraña. No existen estudios previos que comparen la efectividad de ambos fármacos. Objetivo. Comparar parámetros de efectividad en grupos independientes de pacientes tratados preventivamente con uno de los fármacos del estudio a los que se aplicó el mismo protocolo. Pacientes y métodos. Se seleccionó a pacientes con migraña episódica (criterios de la Sociedad Internacional de Cefaleas del 2004) que se habían sometido a tratamiento preventivo por primera vez, con flunaricina (5 mg/día) o nadolol (20-40 mg/día). Se analizaron las variables principales de efectividad (reducción del número de crisis al cuarto mes de tratamiento y tasa de respondedores). Resultados. Se incluyó a 227 pacientes con intención de recibir tratamiento: 155 con flunaricina (80,5% mujeres; edad media: 38,3 ± 12,1 años) y 72 con nadolol (63,8% mujeres; edad media: 37,1 ± 12,0 años). La media de crisis en el mes previo al tratamiento fue de 6,09 ± 2,6 en el grupo de la flunaricina y de 5,1 ± 1,7 en el grupo del nadolol (p = 0,0079); la media de crisis al cuarto mes de tratamiento fue de 2,61 ± 2,4 en el grupo de la flunaricina y de 2,77 ± 2,4 en el grupo del nadolol (p = NS). Porcentaje de reducción de migrañas: 55,2% con flunaricina y 50,4% con nadolol (p = NS). La tasa de respondedores fue del 69% con flunaricina y del 67% con nadolol (p = NS). La tasa de respuesta excelente (reducción mayor o igual al 75% de las crisis) fue del 52,2% con flunaricina y del 36,1% con nadolol (p = 0,0077). Porcentaje de efectos adversos: 48,3% con flunaricina frente a 25% con nadolol (p = 0,0009). La tasa de satisfacción fue del 68%, similar en ambos grupos. Conclusión. Tanto la flunaricina como el nadolol mostraron ser efectivos en el tratamiento preventivo de la migraña episódica. La flunaricina se utilizó con mayor frecuencia en nuestro medio y fue peor tolerada (AU)

Introduction. Flunarizine, with level of evidence A, and nadolol, with evidence level C, would be indicated as preventive treatment of migraine. Yet, no previous studies have been conducted to compare the effectiveness of the two drugs. Aim. To compare the effectiveness parameters in independent groups of patients treated preventively with one of the pharmaceuticals from the study, the same protocol being applied in both cases. Patients and methods. The subjects selected for the study were patients with episodic migraine (according to 2004 International Headache Society criteria) who had undergone preventive treatment for the first time, with flunarizine (5 mg/day) or nadolol (20-40 mg/day). The main effectiveness variables (reduction in the number of seizures at four months of treatment and responder rates) were analysed. Results. The study included 227 patients who intended to receive treatment: 155 with flunarizine (80.5% females; mean age: 38.3 ± 12.1 years) and 72 with nadolol (63.8% females; mean age: 37.1 ± 12.0 years). The mean number of seizures prior to treatment was 6.09 ± 2.6 in the flunarizine group and 5.1 ± 1.7 in the nadolol group (p = 0.0079); at four months of treatment it was 2.61 ± 2.4 in the flunarizine group and 2.77 ± 2.4 in the nadolol group (p = NS). Percentage of reduction of migraines: 55.2% with flunarizine and 50.4% with nadolol (p = NS). The responder rate was 69% with flunarizine and 67% with nadolol (p = NS). The excellent response rate (reduction in the number of seizures by 75% or more) was 52.2% with flunarizine and 36.1% with nadolol (p = 0.0077). Percentage of adverse side effects: 48.3% with flunarizine and 25% with nadolol (p = 0.0009). The satisfaction rate was similar in both groups, 68%. Conclusions. Both flunarizine and nadolol proved to be effective in the preventive treatment of episodic migraine. Flunarizine is used more often in our milieu and was less well tolerated (AU)

In-vitro permeability of poorly water soluble drugs in the phospholipid vesicle-based permeation assay: the influence of nonionic surfactants.

OBJECTIVES: The aim of this study was to determine the influence of nonionic surfactants on drug permeability using the phospholipid vesicle-based permeation assay (PVPA), which excludes other than trans-membrane diffusion pathways. METHODS: Barrier integrity was monitored both by electrical resistance and permeability measurement of the hydrophilic marker calcein. Permeability of the model drugs ketoprofen and nadolol across the PVPA-barrier was measured by HPLC-UV. Micelle association of the model drugs was determined using ultrafiltration, whereby micelle-bound drug and molecular drug were separated. KEY FINDINGS: The nonionic surfactant poloxamer 188 was demonstrated not to affect barrier integrity. Drug permeability was found depressed in the presence of poloxamer 188 in a concentration-dependent manner. Both drugs were found to associate with poloxamer 188 micelles. The extent of the decrease in permeability correlated mostly, but not in all cases, with the fraction of micelle-bound drug. CONCLUSIONS: Micelle association was one important but not the only factor affecting drug permeability across the PVPA-barrier.

Effect of the non-ionic surfactant Poloxamer 188 on passive permeability of poorly soluble drugs across Caco-2 cell monolayers.

Drug permeability of the model drugs ketoprofen and nadolol across Caco-2 cell monolayers was determined in the absence and presence of the non-ionic surfactant Poloxamer 188 (Pluronic® F68, P-188). Stringent controls confirmed that P-188 in concentrations up to 50 mg/ml did not adversely affect cell viability or monolayer integrity. Equilibrium experiments confirmed that the drugs were merely passively transported. Caco-2 permeability of both drugs was found to be decreased by the surfactant in a concentration-dependent manner. Ultrafiltration revealed that both drugs were associated with surfactant micelles. The systematic investigation of micellization on passive absorption showed that association of drugs with P-188 micelles appears to depress their passive permeability under conditions where other transport mechanisms can be neglected.

[Beta blockers in migraine prophylaxis].

Beta blockers (beta-adrenoceptor blockers) are known to be used for the prophylactic treatment of migraine. The improvement of migraine in the patients who recieved propranolol for angina pectoris revealed the effectiveness of propranolol in migraine prophylaxis. Many clinical trials have confirmed that propranolol is effective in the prophylactic treatment of migraine. Other beta-blocking drugs, namely nadolol, metoprolol, atenolol, timolol and bisoprolol, have also been demonstrated to be effective in the prophylaxis of migraine. In contrast, several beta blockers with intrinsic sympathetic activity (ISA), such as alprenolol, oxprenolol, pindolol and acebutolol, have not been demonstrated to be effective in migraine prophylaxis. In this review, we have descrived the pharmacologic background and pharmacokinetics of the beta blockers that demonstrated a prophylactic effect for migraine will be described. We have also reviewed the results of clinical trials of beta-blocking drugs for migraine.

Development of an on-line extraction turbulent flow chromatography tandem mass spectrometry method for cassette analysis of Caco-2 cell based bi-directional assay samples.

Caco-2 cells are frequently used for screening compounds for their permeability characteristics and P-glycoprotein (P-gp) interaction potential. Bi-directional permeability studies performed on Caco-2 cells followed by analysis by HPLC-UV or LC-MS method constitutes the "method of choice" for the functional assessment of efflux characteristics of a test compound. A high throughput LC-MS/MS method has been developed using on-line extraction turbulent flow chromatography coupled to tandem mass spectrometric detection to analyze multiple compounds present in Hanks balanced salt solution in a single analytical run. All standard curves (P-gp substrates: quinidine, etoposide, rhodamine 123, dexamethasone, and verapamil and non-substrates: metoprolol, sulfasalazine, propranolol, nadolol, and furosemide) were prepared in a cassette mode (ten-in-one) while Caco-2 cell incubations were performed both in discreet mode and in cassette mode. The standard curve range for most compounds was 10-2500 nM with regression coefficients (R(2)) greater than 0.99 for all compounds. The applicability and reliability of the analysis method was evaluated by successful demonstration of efflux ratio greater than 1 for the P-gp substrates studied in the Caco-2 cell model. The use of cassette mode analysis through selected reaction monitoring mass spectrometry presents an attractive option to increase the throughput, sensitivity, selectivity, and efficiency of the model over discreet mode UV detection.

[Correlation between absorption rates of beta-adrenoreceptor antagonists in rat small intestine and their molecular structures].

OBJECTIVE: To study the correlation between the absorption rate constants of beta-adrenoreceptor antagonists in rat small intestinal segments and their molecular structural parameters. METHODS: The net atomic charges and the molecular volumes of 11 beta-adrenoreceptor antagonists were obtained with the semiempirical self-consistent field molecular orbital calculation CNDO/2 method and Mont Carlo method respectively, using the minimum energy conformation obtained from the optimization of the standard molecular geometry with the molecular mechanics MM+ method. The stepwise multiple regression analysis was used to obtain the correlation equations. RESULTS: The absorption rate constants of beta-adrenoreceptor antagonists in rat jejunum or ileum were well linearly correlated with the sum of the net charges of all hydrogen atoms and the molecular volumes. The beta-adrenoreceptor antagonist with higher lipophilicity, weaker hydrogen-bonding potential,and smaller molecular volume had greater absorption rate constants. CONCLUSION: The absorption rate constants of beta-adrenoreceptor antagonists in rat small intestinal segments are mainly related with their lipophilicity,hydrogen-bonding potential and molecular size.

Common solubilizers to estimate the Caco-2 transport of poorly water-soluble drugs.

Solubilizers are often used to enhance the bioavailability of drugs with poor aqueous solubility. This study focuses on the use of the Caco-2 system containing solubilizers to predict the absorption of poorly water-soluble drugs in humans. First, the effects of propylene glycol (PG), hydroxypropyl-beta-cyclodextrin (HP-beta-CD), polyethylene glycol 400 (PEG 400), and Tween 80 on the viability (transepithelial electrical resistance, TEER) of 3-day cultured Caco-2 monolayers were evaluated. These solubilizers, even at the low concentration, reduce the viability of Caco-2 monolayers; these results indicate the impossibility for 3-day cultured Caco-2 monolayers to be used for this test. Next, the effects of PG, Tween 80, PEG 400, HP-beta-CD, Pluronic F-68 (Pluronic), HCO-40, sodium lauryl sulfate (SLS), Gelucire 44/14, Transcutol P, and extract gall powder on the viability of 21-day cultured Caco-2 monolayers and the apparent permeability (P(app)) of propranolol (PPL), Nadolol (NDL), and FITC-dextran 4000 (FD-4) were investigated. Five different solubilizing methods (20% PG, 5% Tween 80, 5% PEG 400, 5% HP-beta-CD, and 5% Tween 80+5% PEG 400) did not affect the viability of 21-day cultured Caco-2 monolayers. Furthermore, the P(app) values of the three compounds containing these solubilizers did not differ from the values for control formulations (without solubilizers). These results clearly suggest that the use of PG, Tween 80, PEG 400, or HP-beta-CD as solubilizing excipients and the testing of these formulations on 21-day cultured Caco-2 monolayers can predict intestinal absorption of poorly water-soluble drugs in humans.

Memory for emotional material: a comparison of central versus peripheral beta blockade.

The connection between affect and memory is poorly understood. A possible psychopharmacological linking mechanism is the sympathetic arousal that occurs in response to threatening or emotive material. Cahill et al. (1994) reported that a single administration of 40 mg propranolol hydrochloride, a non-selective beta-adrenergic blocker, to healthy young adults significantly reduced delayed recall of emotive material, with recall of matched neutral material unaffected. This study differed importantly from the original Cahill et al. (1994) procedure in that only the emotionally arousing narrative was employed. Using the same slide presentation as Cahill et al. (1994), an experiment was carried out in order to determine whether beta-adrenergic blockade significantly reduces recall of emotive material via a central or peripheral mode of action. Thirty-six healthy young adults were recruited as subjects. Subjects were randomly allocated to three groups: (a) placebo (b) 40 mg propranolol hydrochloride (a beta blocker which readily crosses the blood brain barrier) and (c) 40 mg nadolol (a beta blocker which does not cross the blood-brain barrier). The three groups were matched for age, sex, intelligence, personality factors, and general memory functioning. Subjects viewed a series of 11 slides accompanied by a narrative, divisible into three phases. The emotionally arousing component of the narrative was introduced during phase II. Both central and peripheral beta blockade produced the expected effects on the sympathetic nervous system, as demonstrated by reliable reductions in systolic and diastolic blood pressure. In a surprise memory test 1 week later, subjects were asked to recall as much as possible of the story and slides, and also completed a forced choice recognition memory test. All three groups showed heightened recall and recognition for the central (emotive) section of the story. There was no differential effect of beta blockade (either central or peripheral) relative to placebo. Beta blockade markedly reduced systolic and diastolic blood pressure, but resulted in no significant effect on memory for both emotional and neutral material.

Bioequivalence of chiral drugs. Stereospecific versus non-stereospecific methods.

Guidelines for bioequivalence of non-racemic pharmaceuticals are abundant in the literature. However, few guidelines exist for the bioequivalence of racemic drugs which consist of 2 or more stereoisomers. The aim of this article is to address the question of whether the bioequivalence of racemic drugs should be based on the measurement of the individual enantiomers or that of the total drug. Several pharmacokinetic-pharmacodynamic cases are examined to test the validity of extrapolating the bioequivalence of racemic drugs to that of their individual enantiomers after administration of the racemate; simulation and experimental data are presented to support these cases. It is shown that for drugs which exhibit non-linear pharmacokinetics, the results of bioequivalence studies based on the total drug may differ from those based on the individual enantiomers. Similar discrepancies can be shown for a racemic drug with linear pharmacokinetics whose enantiomers substantially differ from each other in their pharmacokinetic parameters. Therefore, it is suggested that stereospecific assays be used for these drugs. Additionally, it is recommended that for racemic drugs which undergo chiral inversion, and for most products with modified release characteristics, the bioequivalence be assessed using stereospecific assays. Conversely, for racemic drugs with linear pharmacokinetics and minimal to modest stereoselectivity in their kinetic parameters, and for those with non-stereoselective pharmacodynamics, the use of stereospecific analytical methods are not warranted. Finally, the limited, controversial literature in favour of or against the use of stereospecific assays in bioequivalence of chiral drugs are reviewed and a preliminary guideline is proposed.