1. The metabolic fate of N,N-dimethylcarbamoylmethyl 4-(4-guanidino[14C]benzoyloxy)phenylacetate methanesulphonate (14C-camostat mesylate) was investigated after i.v. administration to man (12-h infusion), and to rat and dog (bolus injection). 2. Renal excretion (mainly in 24 h) accounted for at least 80% dose in all three species, and the only two important metabolites were identified as 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA) and 4-guanidinobenzoic acid (GBA). 3. Parent drug was not detected in human plasma either during or after infusion of 14C-camostat mesylate owing to rapid hydrolysis of the side-chain ester group (t1/2 < 1 min). Steady-state levels of both GBPA and GBA in plasma were apparently attained by the end of the infusion period. Mean terminal half-life, systemic clearance and apparent volume of distribution at steady-state of GBPA in man were 1.0 h, 6.4 ml/min per kg and 0.38 l/kg, respectively, and the corresponding values for GBA were 2.4 h, 4.7 ml/min per kg and 1.01/kg respectively. 4. Radioactivity was rapidly distributed to most tissues after bolus i.v. doses of 14C-camostat mesylate to rats and dogs, with highest levels being associated with the liver and kidney, the two main organs of drug elimination. Concentrations in the pancreas, a possible site for drug action, were generally lower than those in plasma.
The absorption, distribution, metabolism and elimination of the anti-epileptic drug lacosamide were determined in 10 healthy male volunteers following intravenous or oral administration in a single-center, open-label, single-dose trial. Volunteers were randomized to receive either a continuous intravenous infusion of 100 mg (40 μCi) [¹⁴C]-lacosamide administered over 60 min, or a 100 mg (40 μCi) [¹⁴C]-lacosamide dose given as an oral solution. During the infusion, total radioactivity concentrations reached peak levels at 1 h post dose followed by a decline of 71 % within 24 h. More than 97 % of radioactivity was excreted within 168 h; 96.8 % in urine and 0.3 % in feces. Following oral administration, total radioactivity concentrations increased to peak levels within 0.5 h followed by a decline of 65 % within 24 h. Approximately 94.6 % of radioactivity was excreted within 168 h after oral administration, 94.2 % by the kidneys and 0.4% in feces. A comparison of AUC values (po/iv) of unchanged lacosamide indicates a high absolute bioavailability. The metabolic profile was analyzed using pooled urine samples, and following intravenous and oral administration, respectively, a total of 38 and 34 % unchanged lacosamide, 28 and 28 % of the desmethyl metabolite and 19 and 17 % of a polar fraction were measured. Additional metabolites were identified only in small amounts (<3 %). In plasma at maximum concentration, most of the total radioactivity was found as unchanged drug after intravenous and oral dose. The plasma concentration curves of total radioactivity following intravenous and oral administration were similar.
In a single-blind, randomized, two-way cross-over study with 12 healthy male volunteers, 60 micrograms of prostaglandin E1 (PGE1) or placebo was administered by intravenous infusion during a 120-min period. PGE1, 13,14-dihydro-PGE1 (PGE0) and 15-keto-PGE0 plasma concentrations were measured by a highly specific and sensitive GC-MS/MS method. Endogenous PGE1 plasma concentrations ranged between 1.2 and 1.8 pg.ml-1. Endogenous PGE0 and 15-keto-PGE0 plasma concentrations varied from 0.8 to 1.3 pg.ml-1 and from 4.2 to 6.0 pg/ml respectively. During intravenous infusion of PGE1, plasma PGE1 concentrations rose to a level twice as high as during the placebo infusion. In contrast, PGE0 plasma concentrations were 8 times higher during PGE1 infusion than during placebo infusion, and 15-keto-PGE0 plasma concentrations were 20 times higher. The new analytical method has thus been useful to describe the pharmacokinetics of PGE1 and its metabolites PGE0 and 15-keto-PGE0, during and after intravenous infusion of PGE1.
The concentration of thiocyanate in the serum of eight test subjects with renal failure and seven healthy control subjects was measured, as it declined with time, after oral doses of thiocyanate or i.v. injections of nitroprusside had been administered. Additional measurements were taken, on the healthy subjects only, of the concentrations of thiocyanate in the urine, and also of the influence of an increased chloride intake on the rate of elimination of thiocyanate. For the healthy subjects an elimination half-life of between one and five days (mean c. 3 days) was found. Increasing the chloride elimination rate to approximately twice normal did not significantly speed up the rate of thiocyanate elimination. The amounts of thiocyanate which had been administered as doses reappeared almost exclusively in the urine. For the subjects with renal failure, the elimination half-life had a mean value of approximately nine days. The elimination constants were found to be proportional to the creatinine-clearance rates. The ke value at a creatinine-clearance of zero ml/min was approximately 15% of the ke value at a creatinine-clearance rate of 120 ml/min. The distribution volumes for thiocyanate were greater for the patients with renal failure than for the healthy subjects. The conclusions for therapies using nitroprusside are discussed.
Two open-label, randomized, multiple-dose clinical studies evaluated the potential for pharmacokinetic interaction between the antiepileptic drugs lacosamide and valproic acid. The influence of lacosamide on valproic acid pharmacokinetics (trial A) and valproic acid on lacosamide pharmacokinetics (trial B) was investigated in 32 healthy male volunteers, 16 in each trial. Volunteers in trial A received valproic acid (300 mg bid) with randomization to either early or late addition of lacosamide (200 mg bid). Those in trial B received lacosamide (200 mg bid) with randomization to either early or late addition of valproic acid (300 mg bid). Area under the concentration-time curve during a 12-hour dosing interval at steady state (AUC(τ,ss)) and maximum steady-state plasma drug concentration (C(max,ss)) were measured for each drug alone and together and tested for equivalence. The point estimates (90% confidence intervals) for AUC(τ,ss) and C(max,ss) were 104% (99%-109%) and 101% (97%-107%), respectively, for valproic acid and 100% (98%-103%) and 101% (96%-107%), respectively, for lacosamide, which were within the generally accepted equivalence range of 80% to 125%. No changes in the rate or extent of absorption, terminal half-life, or time to maximum concentration were observed. These results suggest that lacosamide and valproic acid have no relevant pharmacokinetic drug-drug interaction.
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