Br. J. clin. Pharmac. (1981), 12, 405-409

METABOLISM AND PHARMACOKINETICS OF DOTHIEPIN

K.P. MAGUIRE, G.D. BURROWS, T.R. NORMAN & B.A. SCOGGINS' Department of Psychiatry and 'Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Parkville, Australia.

1 Seven healthy volunteers received a single oral dose of 75 mg dothiepin. Plasma concentrations of dothiepin were measured by gas chromatography-mass fragmentography. 2 The plasma concentrations obtained were fitted to the equation C, = Ae a(t T) + Be d 7) - Ce ka(t-TI. The mean peak concentration was 47(33-71) ,ug/l at 3(2-5) h. Mean estimates were as follows: absorption half life 1.2(0.07-3.0) h, distribution half-life 2.6(1.1-3.8) h, elimination half-life 22(14-40) h, apparent volume of distribution 45(20-92) 1/kg, and oral clearance 1.36(0.88-1.8)1 kg-' h-'. 3 Blood concentrations of dothiepin were measured in comparison in five of the volunteers. The mean blood/plasma ratio was 0.7(0.6-0.8). , 4 Plasma and blood concentrations of northiaden and blood concentrations of dothiepin S-oxide, two metabolites of dothiepin, were also measured. Dothiepin S-oxide was the major metabolite reaching a peak level of 81(34-150) ,ug/l at 5(4-6) h. In comparison, northiaden reached a peak concentration of only 10 (3-21) ,g/l at 5 (4-9) h. The mean half-life of elimination of dothiepin S-oxide was 19 (13-35) h while that for northiaden was 33 (22-60) h.

Introduction Dothiepin (Prothiaden, Boots) is one of the There has been little data published on either the . It is structurally similar to amitrip- metabolism or pharmacokinetics of dothiepin in tyline and as shown in Figure 1. It possesses man. Crampton et al. (1978) found that the major metabolites recovered from urine were the S-oxides of dothiepin and northiaden (desmethyldothiepin). Only one pharmacokinetic study has been carried out (Rees, 1980). The present study was undertaken to investigate the kinetics of dothiepin following a single oral dose of 75 mg. In addition, concentrations of two metabolites, dothiepin S-oxide and northiaden were CH2 measured. fH2 Methods zN H3C CH3 Seven healthy volunteers, six males and one female, took part in the study after giving informed consent. X = CH2 Their mean age was 26 years (23-29) and their mean X = S Dothiepin weight was 69 kg (63-83). Two hours after a light X = 0 Doxepin breakfast, the volunteers ingested three 25 mg Figure I The structure of dothiepin in relation to dothiepin capsules. A light sandwich lunch was amitriptyline and doxepin. allowed 5-6 h after administration of the drug. Blood samples were taken prior to the dose, then similar properties to the established hourly for 9 h, from an indwelling heparinised , but both the incidence and severity of side catheter in an arm vein. A further six samples were effects has generally been less (Lambourne & Rees, taken by venepuncture over the next 48 h. 1974; Wheatley, 1976). Samples were taken into heparinised tubes then 0306-5251/81/090405-05 $01.00 ©) Macmillan Publishers Ltd 1981 406 K.P. MAGUIRE, G.D. BURROWS, T.R. NORMAN & B.A. SCOGGINS divided into two parts. One part was stored frozen as centrations and times to reach the peak for each whole blood, the other centrifuged and the plasma individual are given in Table 3. separated and stored frozen. Only plasma was kept The mean plasma concentrations of dothiepin and for the first two volunteers. northiaden obtained following the dose are shown in Blood and plasma samples were analysed for Figure 2. The mean blood concentrations of dothie- dothiepin, northiaden and dothiepin S-oxide by gas pin, northiaden and dothiepin S-oxide are shown in chromatography-mass fragmentography (Maguire et Figure 3. Peak concentrations and time to reach the al., 1981). The methodology showed good precision peak, and elimination half-lives for dothiepin S-oxide over the concentration range (2-100 ,ug/l) and the and northiaden are listed in Table 4. limit of sensitivity was 1 ug/l. Within each volunteer, the blood/plasma ratio was The kinetics of dothiepin were examined using a two consistent for each of the three compounds. How- compartment open model. The blood or plasma con- ever, the ratio was not the same for each of the three centrations of dothiepin were fitted to the equation compounds. The mean ratio for dothiepin was C = Ae-a(t-T) +Be-(t-t)-Ce-ka(t-T) by computer 0.72(0.59-0.84) while the mean ratio for northiaden (Cyber 73) using a non-linear least squares fitting was 1.14(0.62-1.57). Plasma concentrations of program. Half-lives of absorption (T.12 abs), distri- dothiepin S-oxide were not quantitated accurately, bution (T./ dist) and elimination (T1,2f3) were however the blood concentrations appeared higher calculated from 0.693/ka, 0.693/a, and 0.693/,8 than the concentrations in plasma. respectively. The area under the concentration time curve (AUC) was estimated using the trapezoidal rule and the infinite part calculated as the last measured concentration divided by ,8. The apparent volume of Discussion distribution (Vd,8) was calculated as the dose. f/AUC.,3 and the oral clearance (Cs) as the dose, The time course of the plasma (or blood) concentra- f/AUC. The fraction, f, which represents that part of tions of dothiepin following oral administation could the dose remaining after losses due to incomplete be described as the algebraic sum of three exponen- absorption, or first-pass metabolism, was assumed to tials with a lag time prior to the absorption phase. be 1. This is consistent with a two compartment open phar- macokinetic model (Wagner, 1975). Results The lag time was close to 1 h in all but one individ- ual. Absorption was rapid as shown by the mean The plasma and blood concentrations of dothiepin half-life of absorption of 1.2 h (blood 1.6 h). The were fitted to the triexponential equation as des- values for A and a in some instances seemed very cribed in Methods. The concentrations were weighted large but could probably be due to insufficient sampl- as l/y and a good fit (r>0.95) was obtained for all ing during the absorption phase. The mean peak con- volunteers. The individual and mean values of A, a, centration of 47 Ag/l (blood 36 ,tg/l) was reached B, /3, ka, r, AUC, Vd,/ and Cs are given in Tables 1 approximately 3 h after the dose. Drug distribution (plasma) and 2 (blood). The absorption, distribution into the tissues was fast as the half-life of distribution and elimination half-lives of dothiepin, the peak con- averaged 2.6 h (blood 2.2 h), but elimination of the

Table 1 Kinetic parameters calculated from plasma concentrations of dothiepin following oral administration of 75 mg.

A B K,, a /3 Lag AUC Vdg Cs Volunteer (Ag/l) (Ag/l) (h-') (h-') (h-1) (h) (pLgl-I h-') (1/kg) (1kg-' h-') 1 59 13 1.05 -0.293 -0.0213 0.95 776 72.0 1.44 2 46 7 10(a) -0.170 -0.0174 0.94 701 91.7 1.60 3 2730 24 0.23 -0.226 -0.0297 0.94 941 42.6 1.19 4 8297 47 0.65 -0.640 -0.0434 0.87 1211 20.4 0.88 5 1455 24 0.44 -0.397 -0.0491 0.00 885 25.4 1.25 6 23 26 10(a) -0.183 -0.0513 0.99 640 27.5 1.41 7 3124 24 0.33 -0.321 -0.0474 0.97 594 38.0 1.80 Mean (1-7) ...b) 24 0.54(c) 0.319 0.0371 0.81 821 45.4 1.36 Mean (3-7) ..4b) 29 0.41(C) 0.353 0.0442 0.75 854 30.8 1.31 (a) Not enough samples to determine accurately due to fast absorption. (b) Mean not calculated as variation between individuals too large. (c) Mean calculated without values for numbers 2 and 6. METABOLISM AND PHARMACOKINETICS OF DOTHIEPIN 407

Table 2 Kinetic parameters calculated from blood concentrations of dothiepin following oral administration of 75 mg.

A B Ka a /3 Lag AUC Vd CS Volunteer (gg/l) (Ag/l) (h-1) (h-') (h-') (h) (lgl-I h-) (I/kg) (1kg- h-1) 3 2758 18 0.21 -0.218 -0.0281 0.91 740 57.2 1.61 4 7500 30 0.51 -0.502 -0.0408 0.82 863 30.4 1.24 5 37 11 1.50 -0.117 -0.0544 0.43 551 33.3 2.00 6 54 19 1.26 -0.509 -0.0595 0.98 380 39.5 2.38 7 2221 15 0.31 -0.307 -0.036 0.84 452 65.8 2.37 Mean --(a) 19 0.76 -0.331 -0.0438 0.80 597 45.2 1.92 (a) Mean value not calculated as variation between individuals too large.

Table 3 Absorption, distribution and elimination characteristics of dothiepin following oral administration of 75 mg. Peak* Volunteer T.2 abs concentration Peak-time T, dist T1fiB (h) (Ag/l) (h) (h) (h) 1 Plasma 0.7 35 2 2.4 26 Blood 2 Plasma 0.07 46 2 4.1 32 Blood 3 Plasma 3.0 33 5 3.1 21 Blood 3.3 29 S 3.2 22 4 Plasma 1.1 71 4 1.1 17 Blood 1.4 53 3 1.4 16 5 Plasma 1.6 60 3 1.8 14 Blood 0.5 38 3 5.9 11 6 Plasma 0.07 44 2 3.8 15 Blood 0.6 30 2 1.4 12 7 Plasma 2.1 40 4 2.2 13 Blood 2.2 28 4 2.3 17 Mean (Plasma) 1.2 47 3 2.6 20 Mean (Blood) 1.6 36 3 2.8 16 *To obtain concentrations in nmol/l multiply by 3.39. drug was much slower with a mean T,,823 of20 h (blood (combining the two studies) whereas a smaller 2.5 16 h). fold variation was found in elimination half-lives. This data agrees well with the study of Rees (1980). Thus the wide range of steady-state concentrations In six volunteers given a single oral dose of 75 mg (20-420 ,tg/l) found after therapeutic doses (Rees, dothiepin, the distribution and elimination half-lives 1980) might be more attributable to the variability in were 2.9 and 23.9 h respectively. Peak plasma con- first-pass metabolism than to elimination rate. A centrations varied from 30-104 ,tg/l as compared to study of dothiepin kinetics following both single and 33-71 gg/l in this study. multiple dosing in patients is being carried out at Estimates of apparent volume of distribution and present. The values obtained for Vd,8 are high (mean oral clearance were lower in the study of Rees (1980). 45 I/kg) but would be considerably lower when cor- This is a result of the differences in area under the rected by f, to account for incomplete absorption and plasma concentration v time curve for the two studies: first-pass metabolism. Considering the high concen- Rees 1560 ,ug 1-' h-'(738-3065) cf. this study 821 ,ug trations of S-oxide present in the early hours post- 1-' h-'. The considerable interindividual variation dose, one would expect that first-pass metabolism in dothiepin concentrations observed in both studies, occurs and that f would be substantially less than one. combined with the small numbers studied might ex- First-pass metabolism has been demonstrated for the plain the discrepant findings. A six-fold interindivid- other tricyclic anti-depressants and ual variation was observed in the area under the curve (Alexanderson, 1972; Gram & Fredric- 408 K.P. MAGUIRE, G.D. BURROWS, T.R. NORMAN & B.A. SCOGGINS

loor 1001

50 501-

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4- 0) &- 10 CU1- 4-a, c 0 .10 ' 10 0 c;05 0 0 0 5 5 E o0 C,,n m

l 0 10 20 30 40 50 60 1l Time after dose (h) 20 30 40 Time after dose (h) Figure 2 The mean plasma concentrations of dothiepin (0*) and northiaden (A) obtained following 75 mg oral Figure 3 The mean blood concentrations of dothiepin dothiepin in seven volunteers. (0), northiaden (A) and dothiepin S-oxide (U) obtained folowing 75 mg oral dothiepin in five volunteers. son-Overo, 1975) and (Maguire et al., 1980). To obtain information on first-pass meta- An in vitro experiment suggested that the whole bolism studies using i.v. administration of the drug blood and plasma concentrations of dothiepin were are necessary. None have been carried out to date. similar (Maguire et al., 1981), hence either biologi- S-oxidation was a more important pathway in the cal fluid could be used to determine pharmacokinetic biotransformation of dothiepin than demethylation. parameters. To verify this, both whole blood and Peak concentrations of dothiepin S-oxide were higher plasma were collected from five of the volunteers. (mean 81 ,g/l or 261 nmol/l) than peak concentra- The blood/plasma in vivo distribution of dothiepin tions of northiaden (mean 10 ,ug/l or 36 nmol/l) in all ranged from 0.59-0.82 and thus the parameters volunteers, and higher than peak concentrations of derived from blood should be used. Plasma derived dothiepin (mean 47 ,g/l or 159 nmol/l) in all but one parameters given an underestimate of apparent volunteer (Tables 3 and 4, Figure 3). Dothiepin and volume of distribution and oral clearance rates its S-oxide were eliminated at a similar rate whilst (Tables 1 and 2). northiaden was more slowly eliminated. Dothiepin was well tolerated at the dose given, the A third metabolite has been identified in human only side effect being drowsiness. The kinetics of the urine following administration of dothiepin drug were similar to the other tricyclic antidepres- (Crampton et al., 1978). This metabolite, northiaden sants in terms of quick absorption, slow elimination, S-oxide, could not be measured by the same pro- large apparent volume of distribution and high oral cedure as used for dothiepin, northiaden and dothie- clearance. Large interindividual variations were ob- pin S-oxide due to different extraction characteristics served, probably due to interindividual variations in (Maguire et al., 1981). Dothiepin S-oxide was not metabolism and elimination of the drug. measured in the plasma samples since at the time of An interesting finding was the high concentrations evaluating the assay methodology, a reference of dothiepin S-oxide. This metabolite has recently sample of dothiepin S-oxide was not available. been found to inhibit uptake of 5HT into platelets However during analysis of the plasma samples for (Norman, Cheng & Burrows, 1980) which is sugges- dothiepin and northiaden concentrations, a major tive of antidepressant activity. Concentrations of this peak was observed. This was subsequently identified metabolite and probably also northiaden S-oxide as dothiepin S-oxide and quantitated in the blood should thus be included in any clinical studies of the samples. drug. Both blood and plasma concentrations of all METABOLISM AND PHARMACOKINETICS OF DOTHIEPIN 409

Table 4 Peak concentrations, peak times and elimination half-lives of dothiepin S-oxide and northiaden following oral administration of 75 mg dothiepin.

Dothiepin S-oxide Northiaden Volunteer Concentration * Time T, /3 Concentration * Time T/,2 3 (Mggl) (h) (h) (GLgll) (h) (h) I Plasma 6 5 19 Blood 2 Plasma 7 3 23 Blood - 3 Plasma 21 8 51 Blood 34 6 17 13 8 60 4 Plasma - 15 9 25 Blood 43 6 35 15 9 32 5 Plasma 3 4 18 Blood 150 4 15 4 4 (a) 6 Plasma 10 4 26 Blood 114 4 1 3 9 6 1 9 7 Plasma 8 4 19 Blood 63 4 14 14 4 22 Mean (Plasma) 10 6 27 Mean (Blood) 81 5 19 11 6 83 (a) Blood concentrations on day 3 were below the sensitivity of the method: not enough data to estimate half-life. *To obtain concentrations in nmol/l multiply by 3.22 for dothiepin S-oxide and 3.56 for northiaden metabolites would also be of interest in view of the The authors would like to thank Ms Pauline Gorban for wide blood/plasma distributions observed for dothi- technical assistance. The study was supported by The Boots epin and northiaden. Co. (Aust) Pty. Ltd and the National Health and Medical Research Council of Australia.

References ALEXANDERSON, B. (1972). Pharmacokinetics of des- NORMAN, T.R., CHENG, H. & BURROWS, G.D. (1980). Pre- methyl- and nortriptyline in man after single liminary studies on the effect of dothiepin and its meta- and multiple oral doses-a cross over.study. Eur. J. clin. bolites on uptake by human blood platelets in Pharmac., 5, 1-10. vitro. Proceedings of the 2nd International meeting on CRAMPTON, E.L., DICKINSON, W., HARAN, G., MAR- Clinical Pharmacology in Psychiatry, Tromso, 20th & CHANT, B. & RISDALL, P.C. (1978). The metabolism of 21st June 1980. Eds. Usdin, E., Dahl, S., Gram, L.F. & dothiepin hydrochloride in vivo and in vitro. Br. J. Phar- Lingjaerde, 0. Basingstoke, U.K.: Macmillan Pub- mac., 64, 405P. lishers. GRAM, L.F. & FREDRICSON-OVERO, K. (1975). First-pass REES, J. (1980). Clinical interpretation of pharmaco- metabolism of nortriptyline in man. Clin. Pharmac. kinetic data on dothiepin hydrochloride (, Ther., 18, 305-314. Prothiaden). Presented at the 12th Congress ofthe Colle- LAMBOURNE, J. & REES, J.A.- (1974). A general practi- gium Internationale Neuro-Psychopharmacologicum, tioner study of dothiepin and amitriptyline. J. int. med. Gothenburg, 22-26 June 1980. Res., 2, 210-213. WAGNER, J.G. (1975). Fundamentals of clinical pharma- MAGUIRE, K.P., NORMAN, T.R., BURROWS, G.D. & cokinetics. Illinois, USA: Drug Intelligence Publica- SCOGGINS, B.A. (1980). An evaluation of maprotiline- tions. intravenous kinetics and comparison of two oral doses. WHEATLEY, D. (1976). A comparison between dothiepin Eur. J. clin. Pharmac., 18, 249-254. and doxepin in the treatment of depression. Prac- MAGUIRE, K.P., NORMAN, T.R., BURROWS, G.D. & titioner, 216, 581-583. SCOGGINS, B.A. (1981). Simultaneous measurement of dothiepin and its major metabolites in plasma and whole blood by gas chromatography-mass fragmentography. J. Chromatogr., 222, 399-408. (Received September 29, 1980)