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Metabolism and Pharmacokinetics of Dothiepin

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Metabolism and Pharmacokinetics of Dothiepin 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 tricyclic There has been little data published on either the antidepressants. It is structurally similar to amitrip- metabolism or pharmacokinetics of dothiepin in tyline and doxepin 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 Amitriptyline 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 antidepressant properties to the established hourly for 9 h, from an indwelling heparinised tricyclics, 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.
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