Altered Pharmacokinetics of Halofantrine by An Antacid, Magnesium Carbonate
Altered Pharmacokinetics of Halofantrine by An Antacid, Magnesium Carbonate
Altered Pharmacokinetics of Halofantrine by An Antacid, Magnesium Carbonate
Research paper
Altered pharmacokinetics of halofantrine by an antacid,
magnesium carbonate
Sylvester O. Aideloje a, Cyprian O. Onyeji a,*, Nicholas C. Ugwu b
a
Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria
b
Faculty of Clinical Sciences, Obafemi Awolowo University, Ile-Ife, Nigeria
Abstract
This study investigated the in vitro adsorption of halofantrine (Hf) by some antacids. Magnesium carbonate showed the highest
adsorptive effect, the extent of adsorption being up to 83%. Only 4% of Hf adsorbed by the antacid could be eluted with 0.1 M HCl
while no detectable elution occurred with water. Other antacids investigated were magnesium trisilicate and aluminium hydroxide and these
had Hf-adsorption capacities of 23 and 43%, respectively. The effect of magnesium carbonate on the bioavailability of Hf was evaluated in
seven healthy volunteers. The subjects were administered with 500 mg oral dose of Hf–HCl or the same dose of the drug in combination
with 1 g of magnesium carbonate, in a crossover fashion. Blood samples were collected at predetermined time intervals and were analysed
for Hf and its major metabolite, desbutylhalofantrine (Hfm), using high-performance liquid chromatography method. The results showed
that magnesium carbonate significantly prolonged (P , 0.05) the time to reach maximum plasma concentration (Tmax) of Hf. Also the
maximum plasma concentrations (Cmax) of Hf and Hfm were significantly reduced (P , 0.05). Furthermore, there was a reduction in the
area under the curve (AUC) values of Hf and this was as high as 56% (range 1–56%). Results of this study suggest that it may not be
advisable to concomitantly administer Hf with an antacid like magnesium carbonate. 1998 Elsevier Science B.V. All rights reserved
* Corresponding author. Current address: Department of Pharmacy 2.1. In vitro adsorption and elution experiments
Research, Hartford Hospital, Hartford, CT 06102, USA;
e-mail: conyeji@harthosp.org Preliminary experiments were performed to determine
the equilibration time for the adsorption of Hf by antacids. samples were centrifuged immediately for 15 min at
One hundred millilitre volumes of 40 mg/ml concentration 2000 × g to obtain the plasma which was transferred into
of Hf were prepared separately in 1% w/v aqueous suspen- plastic tubes and stored at −20°C until analysed.
sions of aluminium hydroxide, heavy magnesium carbonate The plasma samples were analysed for Hf and its major
and magnesium trisilicate. Flasks containing these prepara- metabolite, desbutylhalofantrine (Hfm), using a sensitive
tions were placed in a water-bath at 37.5°C and 5 ml ali- high-performance liquid chromatography (HPLC) method
quots were taken at 0.25, 0.5, 1, 2, 3, 4, 5, and 6 h. The recently developed in this laboratory [12]. In the method,
samples were centrifuged at 5000 rpm for 5 min and con- sample treatment involved protein precipitation with acet-
centrations of Hf in the supernatants were determined onitrile followed by extraction with hexane–diethylether
spectrophotometrically. Maximum Hf adsorption and equi- (1:1, v/v) under alkaline condition. The organic layer was
libration were found to occur after 4 h of interaction with the transferred into a tapered-end tube and evaporated to dry-
antacids. Consequently, the adsorption and elution studies ness over a stream of nitrogen at 40°C. The extract was
were carried out at 37.5°C and the antacid-Hf mixtures were reconstituted in acetonitrile–1 M HCl (90:10) and injected
allowed to equilibrate for 4 h. Other procedures adopted for onto the HPLC through a Varian manual loop valve injector
the adsorption and elution experiments have been reported fitted with a 50 ml loop. A Varian (Palo Alto, CA) model
[11]. In brief, a duplicated series of flasks containing 100 ml 5000 liquid chromatograph fitted with a fixed wavelength
of different concentrations of Hf in 1% w/v aqueous antacid (254 nm) UV detector was used. Chromatographic separa-
suspensions were prepared. The Hf concentration in the tion was achieved on a 10-mm particle size C-18 column
antacids ranged from 5 to 40 mg/ml. After equilibration, (200 × 4.6 mm i.d.) (Hewlett Packard, Avondale, PA)
the contents of the flasks were centrifuged to obtain the using a mobile phase consisting of methanol–0.05 M potas-
supernatants which were assayed spectrophotometrically sium dihydrogen phosphate (70:30, v/v) with 55 mmol/l
for Hf. The adsorption curves were generated. For the elu- perchloric acid. The pH of the mobile phase was 3.1 and
tion experiment, 100 ml of 1% w/v suspension of magne- it was pumped through the column at a flow rate of 1.3 ml/
sium carbonate with a Hf concentration of 40 mg/ml was min. The detection limits for Hf and Hfm were 2.5 and
equilibrated. Elution of the adsorbed Hf was carried out by 2.0 ng/ml, respectively. The intra- and inter-assay co-
extracting the residue left after centrifugation with 100 ml efficients of variation for both compounds were less than
of 0.1 M HCl or water. Concentrations of the extracted Hf 7% (n = 6) at plasma concentrations of 40 and 400 ng/ml.
were monitored over a 6-h period. Triplicate runs were car- The recovery of both compounds at the same concentra-
ried out. tions was not less 87%. The accuracy of the method
assessed by the deviation of the determined concentration
2.2. Subjects and drug administration from the actual concentration was less than 8% (n = 6)
for both Hf and Hfm at concentrations of 40 and 400 ng/
Seven healthy male volunteers between the ages of 24 ml.
and 31 years and weighing between 57 and 67 kg partici-
pated in this investigation after giving their informed con- 2.4. Data analysis
sent. None of the volunteers was receiving any other drugs
for at least 2 months before this study and all of them were The maximum plasma drug concentrations (Cmax) and the
non-smokers. The volunteers were not allowed to take alco- time to reach these concentrations (Tmax) were estimated by
hol or any other medications throughout the duration of the visual inspection of the concentration − time data. The area
study. The study protocol received the approval of the under the curve (AUC) up to the last determined plasma
Ethics Committee of the Obafemi Awolowo University drug concentration was obtained using the linear trapezoidal
Teaching Hospital. After an overnight fast, 500 mg of method. The extrapolated AUC was estimated from the ratio
Hf–HCl (two tablets of Halfan, Smithkline Beecham, of Ct to b, where Ct is the last determined plasma drug
Lagos, Nigeria), was administered with 100 ml of water to concentration and b is the elimination rate constant. Total
each of the seven volunteers. After a wash-out period of 2 AUC (AUCT) was the sum of the AUC up to the last deter-
months, each of these subjects again received the same dose mined concentration and the extrapolated AUC. b was
of Hf–HCl tablets concomitantly with 1 g of magnesium determined by linear regression analysis of at least three
carbonate suspended in 100 ml of water. points on the terminal elimination portion of the log con-
centration versus time profiles. The elimination half-life (T1/
2.3. Sample collection and analysis 2b) was calculated from the ratio: 0.693/b. The Wilcoxon
matched pairs signed-rank test (two-tailed) was used to
Venous blood samples (4 ml) were drawn before and at 1, evaluate the difference between pairs of data. A P-value
2, 4, 6, 8, 12, 24, 48, 72, 168 and 336 h following admin- of ,0.05 was considered significant. Also, the difference
istration of Hf alone and Hf–antacid combination. The in the extent of Hf gastrointestinal absorption in the pre-
blood samples were collected by venipuncture from the sence and absence of the antacid was further evaluated using
forearm and were placed in heparinised tubes. The blood the confidence interval approach [13].
S.O. Aideloje et al. / European Journal of Pharmaceutics and Biopharmaceutics 46 (1998) 299–303 301
Fig. 2. Mean plasma concentrations versus time profiles of halofantrine (Hf) and desbutylhalofantrine (Hfm) following oral administration of 500 mg of
Hf–HCl alone, and with 1 g of magnesium carbonate, to each of seven volunteers.
302 S.O. Aideloje et al. / European Journal of Pharmaceutics and Biopharmaceutics 46 (1998) 299–303