Br. J. clin. Pharmac. (1990), 30, 621-624
Absolute bioavailability and pharmacokinetics of medifoxamine in healthy humans S. SALEH, A. JOHNSTON & P. TURNER Department of Clinical Pharmacology, St Bartholomew's Hospital, London EClA 7BE
Medifoxamine is a new monoamine re-uptake inhibiting antidepressant drug. Twelve volunteers received 100 mg by i.v. infusion over 15 min and 500 mg by mouth fasting. The treatments were given 1 week apart in a randomised cross-over design. Venous blood samples (10 ml) were taken at intervals for 24 h for h.p.l.c. measurement of serum medifoxamine. A biexponential decline of serum medifoxamine concentration was observed after intravenous administration in all subjects and similar terminal elimination half-lives were observed following both routes, indicating that oral absorption is not ratelimiting. The absolute bioavailability of oral medifoxamine was 21%.
Keywords medifoxamine antidepressant bioavailability pharmacokinetics
Introduction
Methods
Medifoxamine (N,N dimethyl-2,2 diphenoxyethylamine) is a new monoamine re-uptake inhibiting antidepressant which is marketed in France and undergoing clinical investigation elsewhere (Randhawa et al., 1988). Pharmacokinetic studies in animals have shown that [14C]-labelled medifoxamine is rapidly and almost completely absorbed, the absolute bioavailability of parent drug being only 0.25, 0.16 and 0.35 in rat, dog and pig, respectively (Labaune et al., 1984), indicating extensive first-pass extraction and metabolism. Preliminary studies of the pharmacokinetics of medifoxamine following oral and intravenous doses in healthy human volunteers showed that values of AUC and Cm. increased linearly with dose and that half-life, clearance and volume of distribution are not dose-dependent (Saleh et al., 1989a, 1990). Data from our own volunteers and from French patients have shown that very little of the parent drug is excreted in the urine, indicating extensive metabolism.
Subjects Twelve healthy human volunteers (six male, six female), average age 22.3 years (range 19-30), mean weight 66.3 kg (range 51-81) and within 10% of their ideal body weight, consented to participate in the study. The study was approved by the Ethics Committee of St Bartholomew's Hospital. The subjects were screened prior to the start of the study to exclude those with a history of cardiac, renal, hepatic or other medical dysfunction which could represent a hazard to the subject or interfere with the study. The pretrial screen included routine laboratory blood tests, blood pressure measurement and an ECG. The volunteers had not taken any drug for at least 7 days prior to the study. Procedure At 09.00 h, after an overnight fast, the subjects rested supine and a Teflon cannula was inserted
Correspondence: Mr S. Saleh, Department of Clinical Pharmacology, St Bartholomew's Hospital, London EClA 7BE
621
622
S. Saleh, A. Johnston & P. Turner
into the antecubital vein of one forearm and maintained patent with saline. Medifoxamine was given orally in the form of one capsule (500 mg; Laboratoires Anphar-Rolland) with 200 ml of water or intravenously (100 mg; Laboratoires Anphar-Rolland) by infusion over 15 min into the antecubital vein of the other arm. Treatments were given 1 week apart in a randomised cross-over design. The fast was continued for 4 h after dosing.
Samples Venous blood samples (10 ml each) were taken before dosing (0) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12 and 24 h following oral administration, and at 0, 5, 10, 15, 20, 25, 30, 40 and 50 min and at 1, 1.5, 2,2.5,3,3.5,4,4.5,5,6,8,10, 12and24 hafter the start of the intravenous infusion. TIhe blood samples were taken into plain glass tubes. After 20 min of gentle mixing, serum was separated by centrifuging at 3000 rev min-1 for 10 min. Urine was collected from 0-4, 4-8 and 8-24 h after administration. After mixing and recording the volume, 20 ml aliquots were taken. Serum and urine samples were frozen at -20° C until analysed for the drug using a specific h.p.l.c. method (Saleh et al., 1989b). The coefficients of variation of the analytical method were 6% at 100 ,ug 1-1, 13% at 50 p,g 1-1, 27% at 25 ,ug 1-1 and 41% at 10 jig Lt1(n = 10).
Results
Medifoxamine was detected in serum and urine samples in all subjects. Individual serum drug concentration-time curves after i.v. administration were adequately described by a biexponential equation. However the curve of the mean data appears to be triphasic (Figure 1). The distribution-phase was short and terminal elimination half-lives ranged from 2.04.3 h. The mean (± s.d.) serum clearance (CL) was 1000 ± 294 ml min-' and volume of distribution (V) averaged 256 ± 83 1. Urinary excretion of unchanged medifoxamine accounted for 0.3% (s.d. ± 0.35) of the dose and the mean renal clearance of medifoxamine was 2.6 ml min(s.d. ± 2.3). Oral pharmacokinetics
The serum drug concentration-time curve after oral administration declined in a biphasic fashion in all subjects. The drug was rapidly absorbed with a mean apparent absorption half-life of 0.2 h (s.d. ± 0.07) and a maximum serum concentration at 1.5 h (median; range 1-3). Serum medifoxamine concentration declined with a terminal elimination half-life of 2.8 h (s.d. ± 1.04). The amount of drug excreted in the urine unchanged was 0.25% (s.d. ± 0.17) of the dose, and the mean renal clearance was 15 ml min-' (s.d. + 16.3).
Data analysis
Standard kinetic parameters (lag-time, apparent absorption half-life, elimination half-life (t½), area under the curve (AUC), clearance (CL), volume of distribution (V), maximum serum drug concentration (Cmax) and time to peak concentration (tmax) were calculated using STRIPE (Johnston & Woollard, 1983). The renal clearance (CLR) was calculated as:
CLR = Ae (0,24 h) AUC (0,24) Where Ae (0,24) = urinary recovery of medifoxamine over 24 h. AUC (0,24) = area under serum drug concentration-time curve over 24 h. Bioavailability (F) was calculated from: and
F=
AUCo x Div AUCiV Do
|{*d5.!{,l'twk^.ri-:zffJy;:?;S¢x,Iio"!*E4r'S/§0.gsjl.egR2[-t^seS;,:Ctxq>pM1
Absolute bioavailability and pharmacokinetics of medifoxamine in healthy humans S. SALEH, A. JOHNSTON & P. TURNER Department of Clinical Pharmacology, St Bartholomew's Hospital, London EClA 7BE
Medifoxamine is a new monoamine re-uptake inhibiting antidepressant drug. Twelve volunteers received 100 mg by i.v. infusion over 15 min and 500 mg by mouth fasting. The treatments were given 1 week apart in a randomised cross-over design. Venous blood samples (10 ml) were taken at intervals for 24 h for h.p.l.c. measurement of serum medifoxamine. A biexponential decline of serum medifoxamine concentration was observed after intravenous administration in all subjects and similar terminal elimination half-lives were observed following both routes, indicating that oral absorption is not ratelimiting. The absolute bioavailability of oral medifoxamine was 21%.
Keywords medifoxamine antidepressant bioavailability pharmacokinetics
Introduction
Methods
Medifoxamine (N,N dimethyl-2,2 diphenoxyethylamine) is a new monoamine re-uptake inhibiting antidepressant which is marketed in France and undergoing clinical investigation elsewhere (Randhawa et al., 1988). Pharmacokinetic studies in animals have shown that [14C]-labelled medifoxamine is rapidly and almost completely absorbed, the absolute bioavailability of parent drug being only 0.25, 0.16 and 0.35 in rat, dog and pig, respectively (Labaune et al., 1984), indicating extensive first-pass extraction and metabolism. Preliminary studies of the pharmacokinetics of medifoxamine following oral and intravenous doses in healthy human volunteers showed that values of AUC and Cm. increased linearly with dose and that half-life, clearance and volume of distribution are not dose-dependent (Saleh et al., 1989a, 1990). Data from our own volunteers and from French patients have shown that very little of the parent drug is excreted in the urine, indicating extensive metabolism.
Subjects Twelve healthy human volunteers (six male, six female), average age 22.3 years (range 19-30), mean weight 66.3 kg (range 51-81) and within 10% of their ideal body weight, consented to participate in the study. The study was approved by the Ethics Committee of St Bartholomew's Hospital. The subjects were screened prior to the start of the study to exclude those with a history of cardiac, renal, hepatic or other medical dysfunction which could represent a hazard to the subject or interfere with the study. The pretrial screen included routine laboratory blood tests, blood pressure measurement and an ECG. The volunteers had not taken any drug for at least 7 days prior to the study. Procedure At 09.00 h, after an overnight fast, the subjects rested supine and a Teflon cannula was inserted
Correspondence: Mr S. Saleh, Department of Clinical Pharmacology, St Bartholomew's Hospital, London EClA 7BE
621
622
S. Saleh, A. Johnston & P. Turner
into the antecubital vein of one forearm and maintained patent with saline. Medifoxamine was given orally in the form of one capsule (500 mg; Laboratoires Anphar-Rolland) with 200 ml of water or intravenously (100 mg; Laboratoires Anphar-Rolland) by infusion over 15 min into the antecubital vein of the other arm. Treatments were given 1 week apart in a randomised cross-over design. The fast was continued for 4 h after dosing.
Samples Venous blood samples (10 ml each) were taken before dosing (0) and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12 and 24 h following oral administration, and at 0, 5, 10, 15, 20, 25, 30, 40 and 50 min and at 1, 1.5, 2,2.5,3,3.5,4,4.5,5,6,8,10, 12and24 hafter the start of the intravenous infusion. TIhe blood samples were taken into plain glass tubes. After 20 min of gentle mixing, serum was separated by centrifuging at 3000 rev min-1 for 10 min. Urine was collected from 0-4, 4-8 and 8-24 h after administration. After mixing and recording the volume, 20 ml aliquots were taken. Serum and urine samples were frozen at -20° C until analysed for the drug using a specific h.p.l.c. method (Saleh et al., 1989b). The coefficients of variation of the analytical method were 6% at 100 ,ug 1-1, 13% at 50 p,g 1-1, 27% at 25 ,ug 1-1 and 41% at 10 jig Lt1(n = 10).
Results
Medifoxamine was detected in serum and urine samples in all subjects. Individual serum drug concentration-time curves after i.v. administration were adequately described by a biexponential equation. However the curve of the mean data appears to be triphasic (Figure 1). The distribution-phase was short and terminal elimination half-lives ranged from 2.04.3 h. The mean (± s.d.) serum clearance (CL) was 1000 ± 294 ml min-' and volume of distribution (V) averaged 256 ± 83 1. Urinary excretion of unchanged medifoxamine accounted for 0.3% (s.d. ± 0.35) of the dose and the mean renal clearance of medifoxamine was 2.6 ml min(s.d. ± 2.3). Oral pharmacokinetics
The serum drug concentration-time curve after oral administration declined in a biphasic fashion in all subjects. The drug was rapidly absorbed with a mean apparent absorption half-life of 0.2 h (s.d. ± 0.07) and a maximum serum concentration at 1.5 h (median; range 1-3). Serum medifoxamine concentration declined with a terminal elimination half-life of 2.8 h (s.d. ± 1.04). The amount of drug excreted in the urine unchanged was 0.25% (s.d. ± 0.17) of the dose, and the mean renal clearance was 15 ml min-' (s.d. + 16.3).
Data analysis
Standard kinetic parameters (lag-time, apparent absorption half-life, elimination half-life (t½), area under the curve (AUC), clearance (CL), volume of distribution (V), maximum serum drug concentration (Cmax) and time to peak concentration (tmax) were calculated using STRIPE (Johnston & Woollard, 1983). The renal clearance (CLR) was calculated as:
CLR = Ae (0,24 h) AUC (0,24) Where Ae (0,24) = urinary recovery of medifoxamine over 24 h. AUC (0,24) = area under serum drug concentration-time curve over 24 h. Bioavailability (F) was calculated from: and
F=
AUCo x Div AUCiV Do
|{*d5.!{,l'twk^.ri-:zffJy;:?;S¢x,Iio"!*E4r'S/§0.gsjl.egR2[-t^seS;,:Ctxq>pM1
