Clin. Phormacokinet. 29 (6), 431-441. 1995

DRUG DISPOSITION

0312-5963/95/00 12.Q431I S05.50/O

© Adis International Limited. All rights reserved .

Clinical Pharmacokinetics of Zopiclone Christine Fernandez,l,2 Corinne Martin,l Franc;ois Gimenez 1,2 and Robert Farinotti2 1 H6pital Pitie Salpetriere, Service Pharmacie-Pharmacocinetique, Paris, France 2 Universite Paris XI, Departement de Pharmacie Clinique, Chatenay-Malabry, France

Contents Summary ... . . . 1. Formulation . . . . . 2. Analytical Methods 2.1 Liquid Chromatographic Methods . 2.2 Gas Chromatographic Methods .. 2.3 Capillary Electrophoretic and High Performance Thin Layer Chromatographic Methods . . . . . . . . 3. Clinical Pharmacokinetics .. . . . . . . . . . 3.1 Absorption and Plasma Concentrations . 3.2 Distribution .. . . . . . . . . 3.3 Metabolism and Excretion . . . . . . . . . 3.4 Half-Life . . . . . . . . . . . . . . . . .. . 4. Stereoselectivity of Zopiclone Pharmacokinetics in Humans 5. Factors Affecting Zopiclone Pharmacokinetics 5.1 Influence of Physiopathology . 5.2 Drug Interactions . . . . . . . . . . . . . . .

Summary

431 432 432 432 433 · 433 · 434 434 · 435 · 436 436 436 437 437 439

Zopiclone is a cyclopyrrolone hypnotic agent. It possesses a chiral centre and is commercially available as a racemic mixture. Methods involving high performance liquid chromatography (HPLC), gas chromatography, capillary electrophoresis (CE) and high performance thin layer chromatography have been developed for the quantitation of zopiclone and its 2 main metabolites in biological samples. For the chiral determination of the enantiomers of zopiclone and its metabolites, HPLC and CE methods are available. After oral administration, zopiclone is rapidly absorbed, with a bioavailability of approximately 80%. The plasma protein binding of zopiclone has been reported to be between 45 and 80%. Zopiclone is rapidly and widely distributed to body tissues including the brain, and is excreted in urine, saliva and breast milk. Zopiclone is partly metabolised in the liverto form an inactive N-demethylated derivative and an active N-oxide metabolite. In addition, approximately 50% of the administered dose is decarboxylated and excreted via the lungs. Less than 7% ofthe administered dose is renally excreted as unchanged zopiclone. In urine, the N-demethyl and N-oxide metabolites account for 30% of the initial dose. The terminal elimination half-life (tl/,z) of zopiclone ranges from 3.5 to 6.5 hours.

Fernandez et al.

432

The pharmacokinetics of zopiclone in humans are stereoselective. After oral administration of the racemic mixture, C max (time to maximum plasma concentration), AUC (area under the plasma time-concentration curve) and t'l:!z values are higher for the dextrorotatory enantiomer owing to the slower total clearance and smaller volume of distribution (corrected by the bioavailability), compared with the levorotatory enantiomer. In urine, the concentrations of the dextrorotatory enantiomers of the N-demethyl and N-oxide metabolites are higher than those of the respective antipodes. The pharmacokinetics of zopiclone are altered by aging and are influenced by renal and hepatic functions . Drug interactions have been observed with erythromycin, trimipramine and carbamazepine.

Zopiclone - the first compound of the cyclopyrrolone class to be marketed - exhibits the same pharmacological profile as do benzodiazepines, with anticonvulsant, anxiolytic and myorelaxant properties coupled with strong sedative action. Because of its rapid absorption and elimination, zopiclone is used as an hypnotic. For short term use, it is a good alternative to hypnotic benzodiazepines, causing little or no dependence and no rebound insomnia. Zopiclone interacts with yaminobutyric acid (GABA) receptors, inhibiting benzodiazepine binding. Zopiclone is marketed as a racemate; the pharmacological properties of each enantiomer have never been described. Indeed, most pharmacokinetic studies have failed to take into account the specific characteristics of the enantiomers.

1. Formulation Zopiclone, 6-(5-chloro-2-pyridyl)-7 -( 4-methyll-piperazinyl)carbonyloxy-6,7 -dihydro(5H)pyrrolo(3,4-b)pyrazin-5-one (fig. 1), is a cyclopyrrolone available as a white crystalline powder, soluble in most organic solvents (alcohols, toluene, acetonitrile, chloroform, dichloromethane, etc.). It is slightly soluble in water and very unstable in nucleophilic solvents such as methanol or ethanol. For analytical assays, stock solutions are usually prepared in acetonitrile. Zopiclone contains an asymmetric carbon atom. The relationship between absolute configuration and specific rotation has been recently established by Hempel et al.:[l] the (+)-enantiomer has the S © Adis Internotionollirnited. All rights reserved.

configuration while the (-)-enantiomer has the R configuration. Recent studies[2] have shown that zopiclone racemises in basic media but not in biological fluids (e.g. plasma).

2. Analytical Methods Simple and sensitive methods have been developed for the quantitation of zopiclone in biological fluids (plasma, whole blood, urine, breast milk). Some of these methods also measure zopiclone metabolites (N-demethyl-zopiclone and zopicloneN-oxide). Most of these assays measure concentrations of unresolved zopiclone, non-stereospecifically. Liquid-liquid extraction is the most frequently used method to simultaneously extract zopiclone and its metabolites from biological samples, using mainly dichloromethane or chloroform in basic mediaP- 61All methods show good efficiency, with an average zopiclone recovery of 95%. 2.1 Liquid Chromatographic Methods Published high performance liquid chromatography (HPLC) methods for assay of zopiclone and its metabolites are summarised in table I. 2. 1. 1 Non-Stereospecific Methods

All HPLC assays show similar sensitivities and are suitable for plasma concentration monitoring after admini stration of a single dose (7.5mg) of zopiclone. Two methods[5,81 permit the simultaneous determination of zopiclone and its 2 main metabolites Clin. Phormocokinet. 29 (6) 1995

Zopiclone Clinical Pharmacokinetics

433

Zopiclone

O:;~:O-a o I

1\ O=C-N N-H \.........I N-Demethyl-zopiclone

~~:O-C' o

<

11\0 N \.........I CH3

O=C-N

Zopiclone- N-oxide

Fig_ 1_ Chemical structure of zopiclone and the metabolites N-demethyl-zopiclone and zopiclone-N-oxide.

in urine. Other methods require separate HPLC conditions for each compound,l3,9] There is no assay with the necessary sensitivity to detect metabolite levels in plasma after single or multiple therapeutic doses of zopiclone. 2_1_2 Stereospecific Methods

Two types of stereospecific assay have been developed to separate the enantiomers of zopiclone and its metabolites. Two of these assays use direct injection onto a chiral column,!IO,II] and separate only the 2 enantiomers of the parent compound. Another assay, requiring a coupled achiral-chiral chromatography, is able to discriminate between the enantiomers of zopiclone[12] and its 2 metabolitesJ8] On a large scale, zopiclone enantiomers can be separated by crystallisation, using malic acid as the resolving agent,[lll or by semipreparative liquid chromatography,[2] using a chiral stationary phase (Chiracel 00). 2.2 Gas Chromatographic Methods

Several assay methods utilising gas chromatography (GC) [see table I] have been developed,l13-l6] However, because of its high thermo-instability, © Adis International Limited. All rights reserved.

zopiclone is not an ideal candidate for GC analysis. Using mass spectrometry, Boniface et al. identified degradation products appearing during GC assays.[17] Gaillard et al. [15] circumvented these difficulties by transforming zopiclone to one of the compounds described by Boniface et al.,[17] using a specific solid-phase extraction before GC analysis. This method, which has a very high sensitivity, is potentially suitable for pharmacokinetic studies. 2,3 Capillary Electrophoretic and High Performance Thin Layer Chromatographic Methods

The only method developed[l] using capillary electrophoresis (CE) permits the simultaneous separation and quantitation of the enantiomers of zopiclone, N-demethyl-zopiclone and zopicloneN-oxide in human urine, using a chiral selector (cyclodextrin) in the running buffer. Its sensitivity, 6/lglL for each compound, allows drug monitoring after a single oral dose. To date, it has only been used in a pilot study.[1] One high performance thin layer chromatography (HPTLC) assay has been described for the Clin. Pharmacokinet. 29 (6) 1995

434

Fernandez et a/.

Table I. liquid and gas chromatographic assays for the determination of zopiclone and its metabolites in biological fluids Sample

limit of detection

Reference

Stationary phase

Detection method

Liquid chromatography Plasma

lichrosorb Si60 5j.lm

Fluorescence

ND

18

Plasma

Hypersil ODS 3j.lm

Fluorescence

5 j.lg/L

4

Plasma

Radial Pak C18

Ultraviolet

2 j.lg/L

9

Plasma, urine"

Spherisorb ODS2 5j.lm

Ultraviolet

5 j.lg/L

5

Plasma

Nucieosil silica

Fluorescence

5j.lg/L

12

Plasma b

Cellulose carbamate 5j.lm

Fluorescence

ND

12

Whole blood

Bownlee Spheri 5 C 18 5j.lm

Ultraviolet

4 j.lg/L

17

Plasma

Ultrasphere ODS 5j.lm

Ultraviolet

5 j.lg/L

7

Plasma

Nova-Pak C18 4j.lm

Diode array

24.8 j.lg/L

6

b. C

Polymethacryloyl (1 R,25-norephedrine)

Fluorescence

ND

11

b. C

Ultron ES Ovomucoid 5j.lm

Fluorescence

ND

11

Urine"

Nucleosyl cyanopropyl 5j.lm

Fluorescence

10 j.lg/L

8

Urine"

Cellulose carbamate 5j.lm

Fluorescence

ND

8

Plasma b

Chiralcel OD-H 5j.lm

Fluorescence

2.5 j.lg/L

10

Column coated with 3% OV-17 on 100-120 mesh ChromosorbQ

Nitrogen-phosphorus

16

Column coated with Ultra 2 (5% phenylmethyl silicone, film thickness 0.52j.lm)

Electron capture

15

Silica capillary column coated with

Thermoionic

5 j.lg/L

14

Thermoionic

ND

13

Gas chromatography Plasma Plasma

Serum

O. 17j.lm thick 5% methyl phenyl polysiloxane: 95% dimethyl polysiloxane phase Ultra 1 column cross-linked methyl silicone gum. film thickness 0.33j.lm a

Method suitable for the determination of the metabolite (zopiclone-N-oxide and N-demethyl zopiclone) concentrations.

b

Chiral assay.

c

Method has not been applied to the analysis of biological samples. Abbreviation: ND = not determined.

quantitation of zopiclone in urine samples spiked with zopiclone at therapeutic concentrations, but the method has not been applied to urine samples of individuals receiving the drug in clinical studies,!13]

3. Clinical Pharmacokinetics 3.1 Absorption and Plasma Concentrations

Zopiclone is rapidly absorbed from the gastrointestinal tractp,19J In healthy individuals receiving an oral dose of 7.5mg, the observed peak plasma concentrations (54 to 86 /lg/L) were reached in 0.5 to 4 hours (table II). Caille et aJ.l19J have shown that 95% of zopiclone absorption was © Adis International limited. All rights reserved.

completed within I hour. However, this percentage was estimated from an absorption half-life extrapolated from only a few plasma samples collected during the drug absorption phase (at 30, 45 and 60 minutes after administration). When a dose of zopiclone is swallowed in the supine position, its absorption is delayed, but not significantly. [20J In 16 young healthy volunteers, zopiclone bioavailability (expressed as an oral/intravenous ratio) following an oral dose of7 .5mg was approximately 80%. This does not indicate a significant first-pass metabolismp,25J Oral administration of 3.5, 7 and 15mg zopiclone have shown that the pharmacokinetics are Clin. Phormacokinet. 29 (6) 1995

435

Zopiclone Clinical Pharmacokinetics

linear.[3) Houghton et al.[22) showed that repeated once-daily administration did not markedly alter zopiclone peak plasma concentrations nor any of its absorption pharmacokinetic parameters. 3.2 Distribution

Plasma protein binding of zopiclone has been reported, but with conflicting results. Gaillot et al. explained the rapid distribution of zopiclone by low binding to plasma proteins (45% ),l3) However, higher values of bound drug (reaching 80%) have also been reported,l18) These contradictory results could reflect different experimental conditions. Although both studies mentioned here used equilibrium dialysis, the exact characteristics of the apparatus and the type of membranes used by the investigators were not described; Howard et al.[18) did not include the range of concentrations they investigated; in both cases, the source of plasma was not mentioned.

In vitro, zopiclone shows a high affinity for benzodiazepine binding sites in the cerebral cortex, hippocampus and cerebellum. This affinity is similar to that of some benzodiazepines (e.g. diazepam), and explains the ability of zopiclone to displace benzodiazepines from binding sites. Conversely, zopiclone has no affinity for peripheral benzodiazepine-binding sites (e.g. kidney»)26) Byrnes et al. [27) studied the binding of zopiclone in 3 brain regions after administration of single zopiclone doses to mice. They showed that zopiclone was not bound to the benzodiazepine site but to a related site on the GABA A receptor complex. These results are in agreement with those of Trifiletti et aI)28) who found evidence that, compared with benzodiazepines, cyclopyrrolones bind to different sites on the same receptor complex. After intravenous administration of IIC_ zopiclone 7.5mg to healthy individuals, Gaillot et al.[3) found evidence that zopiclone is rapidly dis-

Table II. Mean pharmacokinetic parameters of zopiclone after single-dose administration Reference Caille et al,l191 Channer et al. [201 Femandez et al.[21 1 Gaillot et al.[31

Houghton et al. [221 Matheson et al. [231 Pai1
No. of study participants 10

9 12 16 16 12 (6 men, 6 women) 16(8 men, 8 women) 16 11 12 8

Stanley et al.[41 a

Data obtained from graph.

b c

AUC~ .

Dose (mg) [routel 7.5 [PO) 7.5 [PO)

Cmax (I1g1L) 69 64 a

(h) 0.9 la

15 [PO) 7.5 [[V) 3.75 [PO) 5 [PO)

131

1.6

45 (men) 59 (women) 54 (men) 63 (women)

0.89 (men) 2.59 (women) 1.09 (men) 2.59 (women)

68

1.4 1.6 2

7.5 [PO) 15 [PO) 7.5 [PO) 7.5 [PO) 7.5 [PO) 7.5 [PO)

80 64 869

tmax

AUC24 (I1g1L· h) 387

t'f.!z (h) 3.8

479 865b 554b 219

4.9 5.6 5.2 5.1

421b 809b 411 520

Vss (L)

CL (Uh)

CLR (Uh)

140" 92 102

17.3d 18.5d 13.9" 13.9"

0.70" 0.50 0.82

5.3

105

13.9

0.83

5.0 6.5 4.9 3.5 4.9'

100

14.0

0.79 0.64

V/F.

d CUF. e CLRiF. f \1" calculated at from 4 to 10 hours. g Median value.

Abbreviations: AUC24 = area under the plasma concentration-time curve from zero to 24 hours; AUC~ = area under the plasma concentration-time curve from time zero to infinity; Cmax = peak plasma concentration ; CL = total plasma clearance; CLR = renal clearance; F = bioavailability; IV = intravenous; PO = oral; \1"z = terminal elimination half-life; tmax = time to Cmax; Vss = total volume of distribution at steady-state.

© Adis International Limited. All rights reserved.

Clin. Pharmacokinet. 29 (6) 1995

436

tributed from the vascular compartment to the various body tissues, including the brain. Caille et al)22] confirmed the rapid distribution of zopiclone: 15 minutes after oral administration, concentrations of the drug in saliva were found to exceed those in plasma. The characteristic bitter taste experienced after zopiclone ingestion appears to correspond to its excretion into the saliva at levels exceeding 50 Ilg/L. At oral doses within the therapeutic range of 3.75 to 15mg, the increase in volume of distribution (V) of zopiclone is proportional to increases in zopiclone dose. After intravenous administration of7.5mg, a total V of91.8 ± 8.6litres (mean ± SD) was calculated.[3] The excretion of zopiclone into breast milk was studied in 12 lactating women in the early postpartum period after a single oral dose of zopiclone 7.5mg: the ratio of the areas under the breast milk and plasma concentration-time curves (AVCs) for zopiclone was 0.51 ± 0.09 (range 0.41 to 0.70).f2 3] Pounder et aJ.l29] studied the tissue distribution and postmortem redistribution of zopiclone in a 29year-old woman who committed suicide by taking an overdose of zopiclone. The highest drug concentrations were found in the spleen and adipose tissue. Zopiclone was not significantly distributed into solid organs, leading to stable postmortem concentrations in the blood. 3.3 Metabolism and Excretion

Zopiclone is metabolised in the liver. Metabolic studies in rats, dogs and humans have identified 3 main biotransformation pathways: oxidation, demethylation and decarboxylation.[3] In humans, the 2 major urinary metabolites are zopiclone-N-oxide (9 to 18% of the administered dose) and Ndemethyl-zopiclone (13 to 20% of the administered dose) [fig. 1).[3,21,22] N-Demethyl-zopiclone is inactive; the N-oxide metabolite is active, but to a lesser extent than the parent compound.[25] Both oxidation and demethylation are likely to be meditated by cytochrome P450, but the specific isoforms involved have not been identified. © Adis International Limited. All rights reserved .

Fernandez et al.

In blood, approximately 50% of the administered dose is converted to other inactive metabolites via decarboxylation;[3] these metabolites are partly excreted as carbon dioxide via the lungs.[25] ZopicIone, zopiclone-N-oxide, N-demethyl-zopiclone and the other, inactive metabolites are renally excreted. Less than 7% of the administered dose is excreted as unchanged drug in the urine.[3,21,22] After intravenous administration of 7.5mg of zopiclone to healthy individuals, zopiclone plasma clearance (CL) was estimated at 13.9 Lih while its renal clearance (CL R) was found to be between 0.5 and 0.83 LIh.[3] The low clearance of this drug is consistent with the lack of a significant first-pass metabolism. 3.4 Half-Life

The decrease in zopiclone plasma concentrations may be characterised by a bi-exponential equation of a 2-compartment model[3,22] or by a I-compartment modeJ.f20,24] In healthy individuals, zopiclone terminal elimination half-life (ty,z) was found to range from 3.5 to 6.5 hours (table II). The elimination half-life of the N-oxide metabolite ranges from 3.5 to 6 hours, whereas that of the N-demethyl metabolite approximates 7 to 11 hours)n]

4. Stereoselectivity of Zopiclone Pharmacokinetics in Humans Although structurally identical, enantiomers of chiral drugs may differ in their pharmacokinetic properties, especially with regard to metabolism or distribution. Following the oral administration of 15 and 7.5mg of racemic zopiclone to healthy volunteers, zopiclone pharmacokinetics were found to be stereoselecti ve. [10,21] The mean plasma concentration-time curves of R( - )-zopiclone and S( +)-zopiclone after the administration of 15mg of the racemic mixture (Imovane®) are shown in figure 2,121] Plasma concentrations of S( +)-zopiclone were greater than those of R( - )-zopiclone, resulting in higher values of mean maximum plasma concentration (C max ) and elin. Pharmacokinet. 29 (6) 1995

437

Zopiclone Clinical Pharmacokinetics

120 • Racemic zopiclone o S(+)-zopiclone /:::,. R(-)-zopiclone

100

~

~

'"c:

80

0

~

C 60 OJ c..>

c:

0 c..> (1)

E

40

'" n: (1)

20 0 0

120

240

480

360

600

720

Time (min) Fig. 2. Mean (± SEM) plasma concentrations of racemic zopiclone, R(-)-zopiclone and S(+)-zopiclone after a single oral dose of 15mg racemic zopiclone to 12 healthy individuals.

AUe. S(+)-Zopiclone had a lower V value and a slower apparent clearance (CLlF) than R(-)zopiclone, leading to a longer tY2Z value. Since no differences have been observed between the renal clearances of R( -)- and S( +)zopiclone,[21] a stereoselective metabolism has been proposed as a possible cause of the slower elimination of S( +)-zopiclone Because the chiral centre of the parent drug is retained in N-demethylzopiclone and zopiclone-N-oxide, these metabolites can be followed to investigate the stereoselective metabolism of zopiclone. Despite significant interindividual variability both qualitatively and quantitatively, urinary concentrations of S(+)zopiclone-N-oxide and S( +)-N-demethyl-zopiclone were always greater than those of their antipodespl] In one study participant, Hempel et al.[30] confirmed the predominant elimination of S( +)zopiclone-N-oxide but found higher levels of the R(-) enantiomer for N-demethyl-zopiclone. The preferential metabolism of R(-)-zopiclone has been confirmed in vitro, in microsomes obtained from rat hepatocytesPO] Although the pharmacodynamics of each zopiclone en anti orner have not been investigated, their affinity for benzodiazepine receptor binding sites © Adis International Limited. All rights reserved.

has been determined in vitro: S( + )-zopiclone binding was found to be 50 times greater than that of R( -)-zopiclone. lll ] Other pharmacokinetic processes, such as body distribution or biliary excretion could also be stereoselective, but no data are yet available.

5. Factors Affecting Zopiclone Pharmacokinetics The physiopathological status of a patient may modify zopiclone pharmacokinetics, and interactions may occur between zopiclone and other drugs. 5.1 Influence of Physiopathology

The pharmacokinetics of zopiclone in patients and in healthy volunteers are presented in table III. 5. 1. 1 Effecf of Age

Compared with young, healthy volunteers, elderly individuals had higher values of zopiclone absolute bioavailability (F).13 1J No age-dependant variability in zopiclone absorption rate (expressed as t max values) was reported.13 ] In the elderly population, mean zopiclone volume of distribution at steady-state (V ss) was similar to that obtained in Clin. Phormacokinet. 29 (6) 1995

Fernandez et al.

438

Table III. Influence of physiopathological status on zopiclone pharmacokinetics after oral administration of 7.5mg of zopiclone Reference Gaillot et al. 131 )

Number and status of study participants

Cmax (l!glL)

tmax (h)

AUC~

F

(l!glL· h)

(%)

0.5

45 healthy 8 with hepatic failure

1,b

19 elderly (60-85y)

11>

\1"z (h)

77 ± 13a

5.1

97 ± 39c

8.4 ± 3.5

163 ± 38c

8.1 ±3.5

115 ± 61 c

5.5 ± 3.7

3.5

+43%b

18 with chronic renal failure

Unchangedb

+47%b

Gaillot et al. 13)

6 elderly (65-85y) vs 12 young (20-25y)

Unchangedb

+32%b

Gaillot et a1. 13 )

8men

54.5 ± 20.2

1.0 (0.5-3.0)

8 women

63.5 ± 19.1 (NS)d

2.5 (0.5-4.0) (NS)d

Marc Aun§le et

8 healthy

75.9 ±2.5

437.3±46.8

437.3 ± 46.8

3.5±0.32

al[33)

10 with moderate, chronic renal failure

74.4 ± 6.7 (NS)

2.3 ± 0.6 (NS)

614.9 ± 90.9 (NS)

5.8 ± 1.5 (p < 0.05)

8 with severe, chronic renal failure

67.5 ± 7.4 (NS)

1.1 ±0.3(NS)

656.1 ± 151.6 (NS)

5.3 ± 1.5 (p < 0.05)

Viron et al. 132)

+47%b 74.9± 13.9 78.4 ± 13.2 (NS)d

11 healthy

68.1 ± 14.5

1

411 ± 102

4.77±0.86

7 with chronic renal failure

83.6 ± 42.5 (NS)

2 (p < 0.05)

695.1 ±210.7 (p < 0.01)

7.8±2.1 (p
a

Absolute bioavailability.

b

Compared with healthy individuals.

c

Bioavailability measured as AUC po (of non healthy subgroup)/AUC;v (of healthy individuals).

d

Compared with men

=

=

Abbreviations and symbols: AUC~ area under the plasma concentration-time curve from time zero to infinity; Cmax peak plasma concentration after single-dose administration; F =bioavailability; iv =intravenous; NS =nonsignificant difference (compared with healthy individuals unless otherwise specified) ; po =oral; tmax =time to C max ; t,f.!z =terminal elimination half-life; 1, denotes decrease; i denotes increase.

the younger age group, while the central V was decreased and the peripheral V increased.[3)] In elderly individuals, the tY2Z values of zopiclone and its 2 main metabolites are larger than in younger people.!31] Renal excretion of unchanged zopiclone is significantly increased in the elderly, while the total excretion of its metabolites is reduced, indicating lower metabolite/parent ratios.( 3)] The pharmacokinetic modifications observed in the elderly appear to result from age-dependent changes in their liver and kidney functions. Since zopiclone administration is not approved for children less than 15 years old, no pharmacokinetic data are available for this population. 5. 1.2 Effect of Renal Deficiency

Gaillot (3 ) demonstrated that only severe renal deficiency affected zopiclone pharmacokinetics, slightly increasing the AVC and tY2z values. After repeated daily administration of oral zopiclone © Adis International Limited. All rights reserved.

7.5mg, Viron et al.!32) described higher minimum plasma concentrations (Cmin) in patients suffering from severe chronic renal failure compared with healthy individuals. They did not find evidence of any accumulation of zopiclone. According to Gaillot et al.,13] renal deficiency does not appear to affect zopiclone absorption. However, Marc Aurele et al.[33] have reported longer tmax values in patients with moderate renal failure . As in the elderly, a higher apparent bioavailability has been observed in patients with chronic renal failure, probably because of changes in body fluid volumes.[3)) Conflicting results have been reported concerning the influence of haemodialysis on zopiclone pharmacokinetics. Gaillot (3 ) showed a decrease in zopiclone AVC in patients undergoing haemodialysis for renal insufficiency, while Marc Aurele et a1. 133 ] did not describe any modification in the elin. Phormacokinet. 29 (6) 1995

ZopicIone Clinical Pharmacokinetics

439

plasma clearance of zopiclone. Because of the low molecular weight, moderate protein binding, and limited distribution of zopiclone, the drug would be expected to diffuse through the dialysis membranes, although there is no published evidence of this. 5.1.3 Effect of Liver Deficiency

In patients with compromised liver function, tmax is longer, probably because of alterations in hepatic blood flow.!3l) An overall reduction in hepatic metabolism has also been described, leading to higher plasma concentrations and higher AUe and t Y2z values for zopiclone while the plasma AUe values of the 2 main metabolites are reduced)3l ) 5. 1.4 Effect of Gestation

As zopiclone is not recommended during pregnancy, no data is available on zopiclone in pregnant women. Animal studies have shown that zopiclone does not cross the placenta; there was no modification in zopiclone concentrations and AUe values after single or multiple doses in pregnant rats and rabbits.f3)

5. 1.5 Effect of Gender

In humans, rats and dogs, there is no difference in zopiclone kinetics between males and females.!3) 5.2 Drug Interactions

Drug interactions are presented in table IV. Aranko et aU 34 ) reported altered zopiclone pharmacokinetics, particularly absorption and elimination, with concomitant oral administration of erythromycin. The tY2z value of zopiclone was increased, resulting from a decrease in eL.[34) However, according to these authors, this pharmacokinetic interaction would not be clinically significant in young adults. Seppala!3?] did not report any modification in plasma concentrations of zopiclone when the drug was administered alone or in combination with 0.5 g/kg of alcohol (ethanol). In healthy male volunteers, the effect of low (0.215 g/kg) vs high (0.8 g/kg) doses of alcohol on the pharmacokinetics of zopiclone has been compared.I 35 ] Both doses led to similar values of pharmacokinetic parameters. However, zopiclone pharmacokinetics without concomitant alcohol were not investigated, pre-

Table IV. Drug interactions of zopiclone Reference

No. of study participants

Aranko et al. 134J

10

Cailleet al.[19J

10

Lariviere et al.[351

10

Dose of zopiclone (mg)

Dose of other drug

Zopiclone phannacokinetic parameters

Cmax

t max

AUC_

t1/2Z

(Jlg/L)

(h)

(Jl9/L· h)

(h)

7.5

Placebo

53±4

2 (1-4)

331 ± 40

4.8 ± 0.4

7.5

Ery1hromycin 500mg

73±5 (p =0.013)

1 (0.5-3) [p =0.024)

585 ±60 (p < 0.005)

6.8 ± 0.7 (p =0.013)

7.5

69.5 ± 3.7

0.93 ± 0.11

387.2 ± 17.2

3.8 ± 0.2

7.5

Trimipramine 50mg

63 ± 3.2 (NS)

0.83 ± 0.1 (NS)

331.0 ± 24.5 (NS)

3.8 ± 0.2 (NS)

7.5

Low doses of alcohol

56.94 ± 2.82 2.39 ± 0.2

676.04 ± 61.03

9.56 ± 1.32

57.23 ± 4.61 (NS)

596.11 ± 26.79 (NS)

7.06±0.56 (NS)

V/F (L)

(0 .215 g/kg) 7.5

Saano et al.[361

12

High doses of alcohol (0.8 g/kg)

2.11 ±0.18 (NS)

7.5

Placebo

414.4± 117.7

4.2 ± 1.3

2.5

Diazepam 5mg

343.9± 92.2 (NS)

4.9 ± 2.2 (NS) 119.0 ± 40.5 (NS)

7.5

Lorazepam 1mg

364.1 ± 17.2 (NS)

4.6 ± 2.3 (NS) 118.8 ± 30.2 (NS)

107.3 ± 44.8

Abbreviations: AUC_ = area under the plasma concentration-time curve from time zero to infinity; C max = maximum plasma concentration after single-dose administration; F =bioavailability; NS =nonsign~icant difference compared with zopiclone alone or with placebo; t1;,z =tenninal elimination half-life; tmax =time to C max ; V =volume of distribution.

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Clin. Pharmacokinet. 29 (6) 1995

440

Fernandez et al.

venting a conclusion as to the effect of ethanol on zopiclone pharmacokinetics. In healthy individuals, coadministration of zopiclone and trimipramine resulted in decreased bioavailability of both drugs, by 13.7% and 26.6% respectively, compared with single-agent administration) 191 However, these reductions did not have statistical significance. Other pharmacokinetic parameters were not modified.[ 191 In a double-blind, crossover study,[38 1 coadministration of carbamazepine and zopiclone resulted in slightly modified pharmacokinetics of both drugs, compared with single-drug administration. Zopiclone plasma concentrations were significantly increased, while plasma levels of carbamazepine and its lO,ll-epoxide metabolite were decreased. [381 The interaction between zopiclone and the benzodiazepines diazepam and lorazepam was investigated in 12 healthy volunteers.£381 At therapeutic doses, no alteration in elimination was observed for zopiclone or these benzodiazepines.[ 381

6. Conclusions Zopiclone is an hypnotic agent which is rapidly and almost completely absorbed. It is extensively metabolised by the liver and the lungs and only slightly excreted by the kidneys. Its pharmacokinetics appear to be stereoselective with a preferential metabolism of R( - )-zopiclone. The clinical implications of its stereoselective pharmacokinetics have not been evaluated. Several drug interactions have been described, but they do not appear to be of any clinical consequence.

References I. Hempel G, Blaschke G. Enantioselective determination of zopiclone and its metabolites by capillary electrophoresis. J Chromatogr. In press 2. Fernandez C, Gimenez F, Mayrargue J, et al. Degradation and racemization of zopiclone enantiomers in plasma and partially aqueous solutions. Chirality 1995; 7: 267-71 3. Gaillot J, Heusse D, Houghton GW, et al. Pharmacokinetics and metabolism of zopiclone. Pharmacology 1983; 27 Suppl. 2: 76-91 4. Stanley C, Mitchell P, Kaye CM. Simple and sensitive method for monitoring zopiclone in plasma by high-performance liquid chromatography with fluorescence detection. Analyst 1985; 110: 83-4

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5. Le Liboux A, Frydman A, Gaillot J. Simultaneous determination of zopiclone and its two major metabolites (N-oxide and N-desmethyl) in human biological fluids by reversed-phase high-performance liquid chromatography. J Chromatogr 1987; 417: 151-8 6. Tracqui A, Kintz P, Mangin P. High-performance liquid chromatography assay with diode-array detection for toxicological screening of zopiclone, zolpidem, suriclone and alpidem in human plasma. J Chromatogr 1993; 616: 95-103 7. Royer-Morrot MJ, Rambourg M, Jacob I, et al. Determination of zopiclone in plasma using column liquid chromatography with ultraviolet detection. J Chromatogr 1992; 581 : 297-9 8. Fernandez C, Gimenez F, Baune B, et al. Determination of the enantiomers of zopiclone and its two chiral metabolites in urine using an automated coupled achiral-chiral chromatographic system. J Chromatogr 1993 ; 617: 271-8 9. Miller LG, Leduc BW, Greenblatt DJ. Determination of zopiclone in plasma by liquid chromatography with application to steady-state monitoring. J Chromatogr 1986; 380: 211-5 10. Foster RT, Caille G, Anh Ho Ngoc, et al. Stereospecific highperformance liquid chromatographic assay of zopiclone in human plasma. J Chromatogr 1994; 658: 161-6 II. Blaschke G, Hempel G, Muller WE. Preparative and analytical separation of the zopiclone enantiomers and determination of their affinity to the benzodiazepine receptor binding site. Chirality 1993; 5: 419-21 12. Fernandez C, Baune B, Gimenez F, et al. Determination of zopiclone enantiomers in plasma using a chiral cellulose carbamate column. J Chromatogr 1991; 572: 195-202 13. Ahrens B, Schutz H, Seno H, et al. Screening, identification and determination of the two new hypnotics zolpidem and zopiclone. Arzneim Forsch 1994; 44: 799-802 14. Debruyne D, Lacotte J, Hurault de Ligny B, et al. Determination of zolpidem and zopiclone in serum by capillary column gas chromatography. J Pharm Sci 1991 ; 80: 71-4 15. Gaillard Y, Gay-Montchamp JP, Ollagnier M. Gas chromatographic determination of zopiclone in plasma after solidphase extraction. J Chromatogr 1993; 619: 310-4 16. Kennel S, Kintz P, Tracqui A, et al. Identification and quantitation in plasma of zopiclone by gas chromatography with nitrogen-phosphorus detection. J Chromatogr 1990; 527: 169-73 17. Boniface PJ, Martin IC, Nolan SL, et al. Development of a method for the determination of zopiclone in whole blood. J Chromatogr 1992; 584: 199-206 18. Howard PJ, McLean E, Dundee Jw. High performance liquid chromatography and fluorescence detection in the estimation of zopiclone in plasma samples. Proceedings of the British Pharmacology Society; 1985 Dec 18-20. Br J Clin Pharmacol 1986; 21 (5): 614 19. Caille G, Dufouich P, Spenard J, et al. Pharmacokinetic and clinical parameters of zopiclone and trimipramine when administered simultaneously to volunteers. Biopharm Drug Dispos 1984; 5: 117-25 20. Channer KS, Dent M, Roberts CJc. The effect of posture at the time of administration on the central depressant effects of the new hypnotic zopiclone . Br J Clin Pharmacol 1984; 18: 879-86 21. Fernandez C, Maradeix V, Gimenez F, et al. Pharmacokinetics of zopiclone and its enantiomers in Caucasian young healthy volunteers. Drug Metab Dispos 1993; 21: 1125-8 22. Houghton GW, Dennis MJ, Trempleton R, et al. A repeated dose pharmacokinetic study of a new hypnotic agent, zopiclone. Int J Clin Pharmacol TherToxicol 1985; 23: 97-100

Clin. Pharmacokinet. 29 (6) 1995

441

Zopic1one Clinical Pharmacokinetics

23. Matheson I, Sande HA, Gaillot J. The excretion of zopiclone into breast milk. Br J Clin Pharmacol1990; 30: 267-71 24. Parker G, Roberts CJc. Plasma concentrations and central nervous system effects of the new hypnotic agent zopiclone in patients with chronic liver disease. Br J Clin Pharmacol1983; 16: 259-65 25 . Goa KL, Heel RC. Zopiclone: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy as an hypnotic. Drugs 1986; 32: 48-65 26. Blanchard J C, Boireau A, Julou L. Brain receptors and zopiclone. Pharmacology 1983; 17 Suppl. 2: 59-63 27. Byrnes lJ, Greenblatt DJ. Benzodiazepine receptor binding of non-benzodiazepines in vivo: alpidem, zolpidem and zopiclone. Brain Res Bull 1992; 29: 905-8 28. Trifiletti RR, Snyder SH. Anxiolytic cyclopyrrolones zopiclone and suriclone bind to a novel site linked allosterically to benzodiazepine receptors. Mol Pharmacol 1984; 26: 458-69 29. Pounder DJ, Davies JI. Zopiclone poisoning: tissue distribution and potential for postmortem diffusion. Forensic Sci Int 1993; 65: 177-83 30. Hempel G, Blaschke G. Enantioselective metabolism of zopiclone in vitro and in vivo. Presented at 5th International Symposium on Chiral Discrimination; Stockholm, 1994 31 . Gaillot J, Le Roux Y, Houghton GW, et al. Clinical factors for pharmacokinetics of zopiclone in the elderly and in patients with liver and renal insufficiency. Sleep 1987; IO Suppl. 1: 7-21 32. Viron B, De Meyer M, Le Riboux A, et al. Steady state pharmacokinetics of zopiclone during multiple oral dosing (7.5

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33.

34.

35 .

36.

37.

38.

mg) in patients with severe chronic renal failure. Int Clin Psychopharmacol1990; 5 Suppl. 2: 95-104 Marc Aurele J, Caille J, Bourgoin J. Comparison of zopic1one pharmacokinetics in patients with impaired renal fonction and nomal subjects. Effect of hemodialysis. Sleep 1987; 10 Suppl. I: 22-6 Aranko K, Luurila H, Backman JT, et al. The effect of erythromycine on the pharmacokinetics and pharmacodynamics of zopic1one. Br J Clin Pharmacol 1994; 38: 363-7 Lariviere L, Caille G, Elie R. The effects of low and moderate doses of alcohol on the pharmacokinetics parameters of zopic1one. Biopharm Drug Dispos 1986; 7: 207- IO Saano V, Hansen PP, Paronen P. Interactions and comparative effects of zopiclone, diazepam and lorazepam on psychomotor performance and elimination pharmacokinetics in healthy volunteers. Pharmacol Toxicol 1992; 70: 135-9 Seppala T, Nuotto E, Dreyfus JF. Drug alcohol interactions on psychomotor skills: zopic1one and flunitrazepam. Pharmacology 1983; 27 Suppl. 2: 127-35 Kuitunen T, Mattila MJ, Seppala T, et al. Actions of zopic1one and carbamazepine, alone and in combination on human skilled performance in laboratory and clinical tests. Br J Clin Pharmacol1990; 30: 453-61

Correspondence and reprints: Dr Frant;ois Gimenez, H6pital Pitie Salpetriere, Service Pharmacie-Pharmacocinetique, 47-83 Boulevard de I'H6pital, 75651 Paris Cedex, France.

Clin. Pharmacokinet. 29 (6) 1995