Moclobemide excretion in human breast milk

Transcription

1 Br. J. lin. Pharma. (199), 29, Molobemide exretion in human breast milk G. PONS', M. P. SCHORLIN2, Y. K. TAM3, C. MORAN', J. P. PFFN2, Ch. FRANCOUAL4, A. M. PDARRIOSS5, J. CHAVINI4 & G. OLIV' Departement de 'Pharmaologie Clinique Perinatale et Pediatrique and 4Maternite Pinard, H6pital Saint- Vinent de Paul, Paris, Frane, 2Hoffmann-La Rohe, Basle, Switzerland, and 5Produits Rohe, Paris, Frane and 3University of Alberta, dmonton, Canada. 1 Six latating white women, aged years, reeived a single oral dose of 3 mg molobemide, between 9. h and 11. h, 3 to 5 days after the delivery of a full term neonate. 2 Complete milk olletions were obtained before, 3, 6, 9, 12 and 24 h after drug administration by means of a breast pump. Venous blood samples were drawn before, and.5, 1, 3, 4.5, 6, 9, 12, 24 h post-dosing. 3 Molobemide, and its major metabolite (Ro ) were measured in milk and plasma samples using h.p.l.. The ative metabolite (Ro ) ould only be deteted in plasma. 4 Molobemide and its metabolites were not detetable in 24 h plasma samples. Cmax, tmax and t½h for molobemide were (mean ± s.d.) 2.7 ± 1.24 mg l-1, 2.3 ± 1.19 h and 2.26 ±.26 h, respetively. 5 The onentrations of molobemide and Ro in milk were highest at 3 h after drug administration and the drug and metabolite were not detetable after 12 h. Ro was not deteted in any milk sample. The perentages of the dose exreted as molobemide and Ro were (mean ± s.d.).57 ±.2% and.31 ±.11%, respetively. An average 3.5 kg breast-fed neonate would therefore be exposed to only a.5 mg kgmolobemide dose (approximately 1% of the maternal dose on the mg kg-' basis). The low amount of molobemide exreted into breast milk is unlikely to be hazardous to sukling infants. Keywords breast milk antidepressant monoamine oxidase inhibitor molobemide Introdution Molobemide, a benzamide derivative, is a new management of postnatal depression. The adreversible monoamine oxidase-a inhibitor vantages of breast feeding in this ondition are (Keller et al., 1987). It possesses an anti- well reognized and physiians are often redepressant effiay omparable with that of lutant to advise disontinuation of breast feedlomipramine, amitriptyline and imipramine ing beause of potential risks to the infant posed (Larsen et al., 1984; Norman et al., 1985; Stabl by the presene of an antidepressant drug in et al., 1989) and superior to that of plaebo mother's milk. The purpose of this study was to (Casahia et al., 1984; Stabl et al., 1989). Most measure the time ourse of molobemide and its patients tolerate molobemide better than tri- metabolites in human milk and to determine the yli antidepressants (Larsen et al., 1984; Stabl exposure of breast-fed neonates after a single et al., 1989). Molobemide might be useful in the 3 mg oral dose. Correspondene: Dr G. Pons, Departement de Pharmaologie Perinatale et Pediatrique, H6pital Saint-Vinent de Paul, 74 Avenue Denfert Rohereau Paris Cedex 14, Frane 27

2 28 G. Pons et al. Molobemide is a weak base (pka 6.3) with an n-otanol/water distribution oeffiient of 62 at a ph of 7.4 and a moleular weight of 269. It is 5% bound to plasma proteins (Shoerlin et al., 1989). Data in normal healthy volunteers indiate a short terminal half life (1 to 2 h), an intermediate learane (39 1 h-1) and a large volume of distribution (1 to kg-') after a 15 mg intravenous dose. The drug is eliminated primarily by metabolism and exhibits non linear kinetis. The absolute bioavailability averages about 6% after a 1 mg oral dose (Shoerlin et al., 1987). Ro , the main metabolite, produed by hydroxylation of the morpholine ring, is inative while Ro produed by N- oxidation of the same ring is ative. Methods Six latating white women, ranging in age from 24 to 36 years, in height from 158 to 172 m and in weight from 48 to 63 kg were reruited to the study. ah subjet was in good health as assessed by medial history, physial examination and routine laboratory tests. The study was performed on day 3 to 5 after delivery of a full term neonate. Mothers nursing twins were exluded. The subjets had not used any mediation known to indue or inhibit drug metabolism, for at least 2 weeks before drug administration and during the study. Written informed onsent was obtained from all subjets prior to the study. The protool was approved by the UR Cohin Port- Royal this Committee. Before the study eah mother agreed to stop nursing her infant for 24 h after drug administration. ah mother reeived a single oral dose of 3 mg molobemide as three 1 mg tablets with 12 ml of water between 9. h and 11. h after a low-fat breakfast. A lunh was served 4 h after drug intake. During the entire blood sampling period, the subjets were allowed light meals whih were low in fat. Breast milk was olleted using an gnell SMB breast eletri pump (AMDA AG, Zug, Switzerland). The working yle of the breast pump is divided into three phases: a short sution phase, during whih the pressure dereases from atmospheri pressure to 52 mm Hg (negative pressure of 24 mm Hg); a short relief phase, bak to atmosphere pressure; a resting phase under slight overpressure of about 1 mm Hg. The sution rhythm is of 48 periods min-'. Milk samples were olleted immediately before dosing and 3, 6, 9, 12, 24 h after drug administration. Available milk was olleted as ompletely as possible from eah breast. Blood samples were drawn, immediately before,.5, 1, 3, 4.5, 6 and 9 h after drug administration in the first two patients. Two additional blood samples were taken, 12 and 24 h post-dosing in the remaining four. Plasma and milk samples were stored at -2 C until analysis. The onentrations of molobemide and its metabolites (Ro ) and (Ro ) in plasma were measured by h.p.l.. (Geshke et al. 1987). Molobemide and Ro were measured in milk using the same h.p.l.. method after a two step extration with butylhloride and an aetonitrile/hexane (1 : 1 v/v) mixture. The detetion limits were as follows: 2, 3 and 3 ng ml - ' in.5 ml of plasma for molobemide, Ro and Ro ; and.25 and.3 mg I - ' in.5 ml of milk for molobemide and Ro , respetively. The interassay reproduibility was as follows: 1.8 to 7.9% and 3.3 to 9.% for molobemide and Ro over the onentration range in plasma (.15 to 2.5 mg 1 - l) and in milk (.35 to.7 mg 1-1), respetively. The apparent elimination half-life (t½,) was alulated by linear regression from the slope of the log linear deay of the 4.5 to 12 h onentration-time points. The area under the molobemide plasma onentration-time urve (AUC) was alulated using the linear trapezoidal rule with extrapolation to infinity using the ratio of the onentration alulated at the last time point divided by the terminal elimination rate onstant. The oral learane (CLO) was alulated as the ratio of the oral dose/auc. The results are expressed as nmeans and standard deviations (s.d.). For t½/2, values of the mean and s.d. are the harmoni mean and the 'pseudo' standard deviation (Lam et al., 1985). Results Milk yield was 44 ± 13 ml 24 h- l and ml/time-point. Mean plasma molobemide and metabolite plasma onentration-time urves are shown in Figure la. Molobemide, Ro , Ro were not detetable in 24 h plasma samples. The maximum plasma onentration of molobemide (Cmax) was observed between.58 and 3.17 h after drug administration (tmax) and ranged from 1.47 to 4.93 mg I - ' (Table 1). The mean i½/2, AUC and oral plasma learane (CLo) values of molobemide were h, ± 3.3 mg I- h and ± h- ', respetively (Table 1). The onentrations of molobemide and its main metabolite Ro exreted in breast

3 Molobemide in breast milk 29 T a ) -W Co C C.), C ( Cu.1.1 Ii ' T b o U.) 1'.1. A.Al o 3 ~ ~ ~ ~ ~~~~6 91'2 Time (h) Figure 1 a) Plasma onentration-time profiles (mean ± s.d.) of molobemide (o), Ro (A) and Ro (O) following a 3 mg oral dose of molobemide in six latating mothers. b) The mean (± s.d.) onentration of molobemide (-) and Ro (A) in breast milk as a funtion of time following a 3 mg oral dose of molobemide in six latating mothers.

4 3 G. Pons et al. Table 1 Parameters desribing the pharmaokinetis of molobemide following a 3 mg oral dose in six latating mothers tmax Cma t½, AUC CLo Subjet (h) (mg 1-') (h) (mgl 'h) (1h-') Mean s.d Table 2 Breast milk exretion of molobemide and Ro following a 3 mg oral dose in six latating mothers Molobemide Ro Cumulative amount % of dose Cumulative amountl Cumulative amount % ofdose exreted in milk exreted plasma A UC ratio exreted in milk exreted (-24 h) in milk (-24 h) in milk Subjet (mg) (%) (I h') (mg) (%) Mean s.d milk were highest 3 h after drug administration and were no longer measurable after 12 h. The milk onentration-time urves paralleled the plasma onentration-time urves (Figure lb). The onentration of molobemide in milk orrelated with its plasma onentration (y = x; r =.986): the slope of this equation indiates that the onentration of drug in milk is, on average, 72% of that in plasma. The perentage of the administered dose exreted in 24 h was.57 ±.2 and % for molobemide and Ro , respetively (Table 2). Ro , an ative metabolite, was not deteted in breast milk. Disussion The experimental design took into onsideration the signifiant hanges, previously desribed (Wilson et al., 198), in milk omposition and yield, whih depend on the time of sampling during a feeding, the side of olletion, the time of the day, the stage of latation and the nutritional state. The sampling protool was standardized to allow interpatient ompansons and also for the measurement to be relevant to linial pratie. Milk was sampled from eah breast as ompletely as possible in order to obtain samples representative of a omplete feed. The time interval between onseutive milk olletions was similar to that of a regular shedule of breast feeding. In all patients the study was performed during the fourth to the sixth days postpartum and at the same time of the day. All of the latating mothers were well nourished and had given birth to a full term neonate. Drug exretion in breast milk is primarily by passive diffusion aross the mammary membranes leading to rapid equilibration of drug between plasma and milk (Wilson et al., 198). Breast milk an, therefore, be onsidered as a

5 ompartment with bidiretional transfer aross a blood-milk barrier rather than a bladder with milk aumulation between two onseutive olletions. We thus hose to onsider eah milk sample as instantaneous, at the mid-point of the milk olletion interval, rather than to onsider the amount of drug reovered as the result of drug aumulation in breast during the time elapsed sine the previous milk olletion. The parallel deline of milk and plasma molobemide onentrations (Figure la and lb) support the hypothesis of rapid equilibration of drug between plasma and milk. The kineti parameters desribing the time ourse of molobemide in plasma in the latating mothers following a 3 mg dose are onsistent with those observed in previous studies in healthy male volunteers (Data on file Hoffmann La Rohe). We have shown that breast-fed neonates from mothers treated with a single 3 mg oral dose of molobemide would be exposed to only a small amount of the drug and its major and inative metabolite Ro when fed as early as 3 h after drug administration. Using the total amounts of ompounds reovered in breast milk over the period of the study, a hild weighing 3.5 kg is estimated to reeive, on average, about.5 mg kg- l molobemide (approximately 1% of the maternal dose on the mg kg- 1 basis) and.28 mg kg'- Ro , assuming that suh a 3-5 day old infant would be able to ingest the Molobemide in breast milk 31 relatively large amount of milk olleted. The amount of molobemide transferred into milk is not expeted to be very muh higher after the 6th day post-delivery due to hanges in milk yield and omposition whih our during maturation. During multiple dosing, aumulation of the ompounds in plasma and breast milk may our. Aumulation in plasma has been demonstrated in healthy volunteers. Furthermore, molobemide exhibits non linear kinetis when given as a 1 mg dose three times daily for 15 days, the steady-state area under the plasma drug onentration-time urve being two times higher than after a single 1 mg dose (Shoerlin et al., 1987). The dosage used in the present study is two to three times higher than a single therapeuti dose. Thus, the AUC obtained in the present study in latating mothers reeiving a single 3 mg dose was similar to that, at steadystate, in healthy volunteers reeiving 15 mg three times daily (Data on file Hoffmann La Rohe). The dosage used in the present study might, therefore, be onsidered as representative of steady-state onditions, suggesting that exposure of breast-fed neonates during a dosing interval of a 15 mg three times daily therapeuti hroni dose is not expeted to be different to that following a single 3 mg dose. The low amount of molobemide exreted into breast milk is unlikely to be hazardous to sukling infants. Referenes Casahia, M., Carolei, A., Barba, C., Frontoni, M., Rossi, A., Meo, G. & Zylberman, M. R. (1984). A plaebo-ontrolled study of the antidepressant ativity of molobemide, a new MAO-A inhibitor. Pharmaopsyhiatry, 17, Geshke, R., Korner, J. & ggers, H. (1987). Determination of the new monoamine oxidase inhibitor molobemide and three of its metabolites in biologial fluids by h.p.l.. J. Chromatogr., 42, Keller, H. H., Kettler, R., Keller, G. and Da Prada, M. (1987). Short-ating novel MAO inhibitors: In vitro evidene for the reversibility of MAO inhibition by molobemide and Ro Naunyn- Shmiedebergs Arh. Pharma., 335, Lam, F. C., Hung, C. T. & Perrier, D. G. (1985). stimation of variane for harmoni mean halflives. J. pharm. Si., 74, Larsen, J. K., Holm, P. & Mikkelsen, Ph. (1984). Molobemide and lomipramide in the treatment of depression. Ata Psyhiatr. Sand., 7, Norman, T. R., Ames, D., Burrows, G. D. & Davies, B. (1985). A ontrolled study of a speifi MAO-A reversible inhibitor (Ro ) and amitriptyline in depressive illness. J. affetive Disord., 8, Shoerlin, M. P., Mayersohn, M. & Korn, A. (1987). Disposition kinetis of molobemide, a mono amine oxidase-a enzyme inhibitor: single and multiple dosing in normal subjets. Clin. Pharma. Ther., 42, Shoerlin, M. P. & Guentert, T. W. (1989). Pharmakokinetik und Metabolismus reversibler MAO-A Hemmer beim Menshen. Psyhiatr. Prax., 16, Stabl, M., Biziere, K., Shmid-Burgk, W. & Amrein, R. (1989). Review of omparative linial trials: molobemide vs triyli antidepressants and vs plaebo in depressive states. J. Neural. Transm., suppl 28, Wilson, J. T., Brown, R. D., Cherek, D. R., Dailey, J. W., Hilman, B., Jobe, P. C., Manno, B. R., Manno, J.., Redetzki, H. M. & Stewart, J. J, (198). Drug exretion in human breast milk: priniples, pharmaokinetis and projeted onsequenes. Clin. Pharmaokin., 5, (Reeived I June 1989, aepted 12 September 1989)