ABSTRACT:The absorption, metabolism, and excretion of the oral direct thrombin inhibitor, ximelagatran, and its active form, melagatran, were separately investigated in rats, dogs, and healthy male human subjects after administration of oral and intravenous (i.v.) single doses. Ximelagatran was rapidly absorbed and metabolized following oral administration, with melagatran as the predominant compound in plasma. Two intermediates (ethyl-melagatran and OH-melagatran) that were subsequently metabolized to melagatran were also identified in plasma and were rapidly eliminated. Melagatran given i.v. had relatively low plasma clearance, small volume of distribution, and short elimination half-life. The oral absorption of melagatran was low and highly variable. It was primarily renally cleared, and the renal clearance agreed well with the glomerular filtration rate. Ximelagatran was extensively metabolized, and only trace amounts were renally excreted. Melagatran was the major compound in urine and feces after administration of ximelagatran. Appreciable quantities of ethyl-melagatran were also recovered in rat, dog, and human feces after oral administration, suggesting reduction of the hydroxyamidine group of ximelagatran in the gastrointestinal tract, as demonstrated when ximelagatran was incubated with feces homogenate. Polar metabolites in urine and feces (all species) accounted for a relatively small fraction of the dose. The bioavailability of melagatran following oral administration of ximelagatran was 5 to 10% in rats, 10 to 50% in dogs, and about 20% in humans, with low between-subject variation. The fraction of ximelagatran absorbed was at least 40 to 70% in all species. First-pass metabolism of ximelagatran with subsequent biliary excretion of the formed metabolites account for the lower bioavailability of melagatran.

No abstract

The pharmacokinetics and antihypertensive effects of felodipine, a new dihydropyridine calcium channel blocker, were studied in elderly hypertensive patients, 67 to 79 years of age and in young healthy subjects, 20 to 34 years of age following oral administration of 5 mg twice daily to steady-state. A single intravenous dose of 3H-felodipine (0.04mg) was given together with the oral dose on the study day. Cmax (17 nmol/L), Cmin (5 nmol/L) and AUC (82 nmol/L.h) were 3 times higher in the elderly than in the young subjects. Systemic availability was about 15% in both groups. Plasma clearance (CL) was reduced from 56.1 L/h in the young to 25.4 L/h in the elderly. There was no effect of age on the volume of distribution at steady-state (Vss). Reduced hepatic blood flow and enzyme activity or increased gut wall metabolism are possible reasons for the altered pharmacokinetics in the elderly. Blood pressure was reduced in the elderly from 190/99 to 177/91 mm Hg 12 hours after 5mg felodipine during twice daily dosage. The effect on blood pressure correlated with plasma concentrations of felodipine.

The biliary secretion of [14C]felodipine in 4 healthy human subjects was studied by use of the multiple marker dilution principle with double lumen tubes placed in the stomach and intestine. Insignificant amounts of 14C activity were recovered from gastric aspirates. The individual recovery from intestinal aspirates varied from 2.9 to 8.5% of the dose of radioactivity over the period of 4.5 h after dosing. Less than 0.1% was identified as unchanged felodipine. The results show that biliary secretion is a minor route of elimination of felodipine or its metabolites. Bile collection for 4.5 h had no significant effect on the pharmacokinetics of felodipine, although the 72 h urinary recovery of radioactivity tended to be lower when bile was collected (59%) than in the control experiment (66%).

1. After i.v. and intraduodenal administration of 3H-felodipine to rats, approx. 50% of the dose was excreted in bile in the first 6 h. Total urinary and biliary recoveries after both administration routes were similar. 2. Neither unchanged felodipine nor oxidized pyridine metabolite was detected in bile. Bile collection had no effect on the blood concentration-time profiles of either compound. 3. Bile collection decreased the area under the blood concentration-time curve (AUC) of total, unidentified felodipine metabolites by 30%, and their urinary recovery by 50%. 4. Of the total metabolites excreted in bile, 40% was calculated to be subject to enterohepatic recycling. 5. The dose-normalized AUC of both felodipine and pyridine metabolite were decreased after intraduodenal administration of drug, indicating pre-systemic elimination of drug, and possibly of the pyridine, in the gut. Route of administration had no effect on the AUC of total unidentified metabolites.

No abstract

The adsorption of ,B-adrenoceptor blockers and the partial f3-adrenoceptor agonist prenalterol was studied in an in vitro haemoperfusion (HP) model. Metoprolol, alprenolol, propranolol and prenalterol adsorb well from the blood to the resin with extraction ratios nearing 1.0. Extraction ratio for practolol was 0.68 and for atenolol 0.49. Protein binding has little effect on the degree of adsorption, which is more dependent on water solubility.

The pharmacokinetics of pafenolol were studied in eight young healthy individuals. The doses were 10 mg iv and 40 mg orally. Each dose was labeled with 100 microCi [3H]pafenolol. The plasma concentration-time curve of the oral dose exhibited dual maxima. The second peak was about four times higher than the first one. Maximum concentrations were attained after 0.9 +/- 0.2 and 3.7 +/- 0.6 hr. The mean bioavailability (F) of the oral dose was 27.5 +/- 15.5%. The reduction in F was due mainly to incomplete gastrointestinal absorption. The drug was rapidly distributed to extravascular sites; t1/2 lambda 1 was 6.6 +/- 1.8 min. The volumes of distribution were Vc = 0.22 +/- 0.08 liter/kg, Vss = 0.94 +/- 0.17 liter/kg, and Vz = 1.1 +/- 0.16 liters/kg. The iv dose of pafenolol was excreted in unchanged form in the urine to 55.6 +/- 5.1% of the given dose and in the feces to 23.8 +/- 5.7% within 72 hr. The corresponding recoveries of the oral dose were 15.8 +/- 5.9 and 67.0 +/- 10.2%, respectively. About 10% of both doses was recovered as metabolites in the excreta. Approximately 6% of the oral dose was metabolized to nonabsorbable compounds in the intestine. The mean total plasma clearance was 294 +/- 57 ml/min, of which renal clearance, metabolic clearance, and gastrointestinal and/or biliary clearance were responsible for 165 +/- 31, 31 +/- 15, and 95 +/- 32 ml/min, respectively. The half-life of the terminal phase determined from plasma levels up to 24 hr after dosing was 3.1 +/- 0.3 hr for the iv dose and 6.7 +/- 0.7 hr for the oral dose.