In vitro metabolic products of RWJ-34130, an antiarrythmic agent, in rat liver preparations.

The in vitro metabolism of RWJ-34130, an antiarrhythmic agent, was conducted using rat hepatic 9000 x g supernatant (S9) and microsomes in an NADPH-generating system, and the rat liver perfusion. The 100 and 20 microg ml(-1) concentrations of RWJ-34130 aqueous solution were used for microsomal incubation and liver perfusion, respectively. Unchanged RWJ-34130 (approximately 77-78% of the sample in both S9 and microsomes) plus a major metabolite, RWJ-34130 sulfoxide (20% of the sample in both S9 and microsomes) were profiled, isolated and identified from both hepatic S9 and microsomal incubates (60 min) using HPLC and mass spectrometry (MS), and by comparison to a synthetic RWJ-34130 sulfoxide, which was synthesized by reacting RWJ-34130 with MCPBA (meta-chloroperoxy benzoic acid). No unchanged RWJ-34130 was detected in the 3 h liver perfusate, however, 1-phenyl-2-oxo-pyrrolidine was profiled, isolated and identified as a major hydrolyzed metabolite of liver perfusate. RWJ-34130 is not extensively metabolized in vitro in rat hepatic S9 and microsomes. All HPLC metabolic profiles of hepatic S9 and microsomal samples (30 min, 60 min) were qualitatively and nearly quantitatively identical.

Disposition of bepridil in laboratory animals and man.

1. The disposition and pharmacokinetics of bepridil (Bp) were studied in mouse, rat, rabbit, rhesus monkey, and man. Bp was essentially completely absorbed by all species. 2. Maximum plasma Bp concentrations were achieved within 2 h of drug administration. Linear but non-proportional, dose-related increases in the area under the curve (AUC) for plasma Bp vs. time were noted after increasing oral doses of Bp.HCl to rats (30-300 mg/kg) and monkeys (25-200 mg/kg). 3. Daily administration of Bp.HCl to rats (100 mg/kg per day for 15 days) and monkeys (200 mg/kg per day for 13 days) produced no statistically significant changes in Bp pharmacokinetic parameters. 4. Oral plasma clearance (CLp) of Bp was very low in man (ca. 0.93 l/h per kg) compared to experimental animals (14.8-63.8 l/h per kg). Terminal elimination half-lives were 1.5-2.0 h for mouse and rat, ca. 4.4 h for monkey and ca. 48 h for man. 5. Bp and a total of 12 metabolites were identified and quantified. Metabolite formation in the five species was adequately described by four interrelated pathways, namely, aromatic hydroxylation, followed by N-dealkylation, N-debenzylation, and N-acetylation. Metabolites produced by this pathway included 4-hydroxy-Bp, N-benzyl-4-aminophenol, 4-aminophenol, and N-acetyl-4-aminophenol. Comparison of the proposed pathways revealed qualitative similarity among species.

Evaluation of drug absorption and presystemic metabolism using an in situ intestinal preparation.

An in situ rat intestinal preparation was modified to include portal and jugular venous blood collection techniques as well as sampling from the intestinal lumen. Viability could be maintained for 3 h. The utility of the preparation was examined by studying the disposition of four model drugs, each with differing characteristics with respect to absorption and presystemic metabolism. Haloperidol (4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1- butanone), a reference compound used for model development, disappeared from the intestinal lumen with a half-life of 14 +/- 3 min. When the antiarthritic agent, tolmetin sodium (sodium 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate dihydrate), was studied in the preparation, it was rapidly absorbed (t1/2 for disappearance from the intestinal lumen = 8 min), achieved plasma concentrations comparable to in vivo data, and underwent little presystemic elimination. In contrast, fenoctimine sulfate (4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine sulfate), an antisecretory compound, disappeared more slowly from the intestinal lumen (t1/2 = 60 min), was present in portal plasma, but was not detected in systemic plasma. Extensive hepatic first-pass elimination of fenoctimine was evident. Tolmetin glycine amide (N-([1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetyl)glycine), a tolmetin prodrug, disappeared from the intestinal lumen very slowly (t1/2 approximately 3 h) compared with the other agents tested. It was determined that this drug was being hydrolyzed presystemically to tolmetin by the intestinal mucosa and the liver. These results establish the utility of this intestinal preparation for studying drug absorption and presystemic elimination.

Disposition of zomepirac sodium in man.

Five healthy male human subjects were administered 200 mg oral solution doses of zomepirac-14C sodium. Plasma and urine samples were analyzed for zomepirac, hydroxyzomepirac, and zomepirac glucuronide. Zomepirac was the major circulating compound, with zomepirac glucuronide and hydroxyzomepirac accounting for the remainder of the radioactivity. Elimination half-lives for zomepirac, zomepirac glucuronide, and hydroxyzomepirac were 7.6, 8.2, and 7.8 hours, respectively. The dose was completely recovered in the urine (95 per cent in 72 hours). Zomepirac glucuronide constituted up to 90 per cent of the urinary radioactivity, with zomepirac and hydroxyzomepirac about 5 per cent each. The urinary zomepirac was probably present as a result of hydrolysis of zomepirac glucuronide. The plasma clearance of zomepirac was 189 +/- 23 ml/min. The metabolites were cleared by the kidney at rates of 343 +/- 88 ml/min (zomepirac glucuronide) and 339 +/- 88 ml/min (hydroxyzomepirac). Thus, metabolic clearance appears to be the sole mode of zomepirac elimination. The metabolites are then rapidly cleared by the kidneys.

Dose-dependent pharmacokinetics and renal handling of zomepirac in rhesus monkeys.

The pharmacokinetics and renal handling of zomepirac, a new analgesic agent, were studied in rhesus monkeys. Single oral 5, 10 and 40 mg/kg doses were administered to fasted male and female rhesus monkeys. After the 40 mg/kg dose, about 2.5-fold higher peak zomepirac plasma concentrations and area under the curve were observed that predicted from the lower doses and plasma clearance decreased from 4.6 to 1.8 ml/min/kg. Because zomepirac is a weak acid and is a substrate for the renal tubular acid transport system, the possible role of concentration-dependent renal clearance was evaluated. Renal clearance of zomepirac averted only 0.007 ml/min/kg and was concentration independent. Essentially all of the plasma clearance was accounted for by formation of the glucuronide conjugate of zomepirac, which was subsequently excreted in the urine. These findings, when placed in perspective with other data, indicate that the nonlinear kinetics of zomepirac in fasted rhesus monkeys are probably due to saturation of metabolism.

The metabolism of zomepirac sodium. I. Disposition in laboratory animals and man.

Zomepirac sodium (ZS) is an orally active, nonnarcotic, analgesic agent. The disposition and pharmacokinetics of zomepirac (Z) were studied in rats, mice, rabbits, hamsters, rhesus monkeys, and healthy human subjects. Z was rapidly and completely absorbed by all animal species and man. Dose-related linear increases in the area under the curve for plasma Z vs. time were noted after increasing po doses of ZS to mice (2.5--7.5 mg/kg), rats (0.5--10 mg/kg), and rhesus monkeys (5--40 mg/kg). Daily administration of ZS to rats (10 mg/kg/day for 10 days) caused no biologically significant changes in the pharmacokinetic profile for Z. Assessment of Z's absolute bioavailability in monkeys (10 mg/kg, iv vs. po) indicated that po doses of ZS were completely bioavailable (F = 1.12 +/- 0.40). Plasma clearance ranged from ca. 4.5 ml/min/kg for the female hamster, rhesus monkey, and man to as low as 0.30 ml/min/kg for rats, mice, and rabbits. Terminal elimination half-lives averaged 5.3--6.6 hr for mouse, 2.8--6.5 hr for rat, 2.5 hr for rabbit, 2.3 hr for hamster, 12.7--25.5 hr for rhesus monkey, and 4 hr for man. The major route of excretion for Z and its metabolites was via the kidneys for all animals and man with the balance appearing in feces. Biliary excretion was qualitatively observed in rhesus monkeys and quantitated in rats (23.6% of dose in 27 hr). Formation of the acyl glucuronide of Z was the major metabolic pathway in man and rhesus monkey, was substantial in the mouse, was very minor in the rat and rabbit, and was nonexistent in the hamster. Rat, mouse, and hamster hydroxylate the 4-methyl group on the pyrrole ring to give hydroxyzomepirac (a biologically inactive metabolite), a minor metabolite in man and nonexistent in the rhesus monkey. The rodents also cleave Z to form 4-chlorobenzoic acid and its conjugates, minor metabolites in man and rhesus monkey.

Renal handling of zomepirac sodium (McN-2783-21-98) in the rat.

The plasma and renal clearance of zomepirac, a weak organic acid, was investigated in anesthetized CR Wistar rats after administration of single bolus i.v. injections or continuous i.v. infusions of the 14C-labeled compound. Adjustment of urine pH to the alkaline range caused more than an 8-fold lowering of the plasma elimination half-life (from 7.0 to 0.8 hr) and enhanced renal clearance by a factor of 53 compared to control. Acidification of the urine or probenecid administration increased the elimination half-life (to 10.9 and 17.5 hr, respectively), and decreased renal and plasma clearance of zomepirac. Since zomepirac is highly bound to plasma proteins (approximately 98%), only a small fraction of the drug is available for filtration at the glomerulus. Therefore, the renal elimination of zomepirac is accomplished mainly by active tubular secretion. Passive nonionic reabsorption is a major factor in determining the net clearance of the drug.

The time course of tolmetin and its metabolites in the plasma of individual rats and mice.

Tolmetin, 1-methyl-(5-p-toluoyl)pyrrole-2-acetic acid, is a new, nonsteroidal, anti-inflammatory agent. After oral administration of tolmetin-14C to rats and mice, sequential microsamples of blood were obtained from the ophthalmic venous plexus via the orbital sinus. Plasma was collected after centrifugation, and microaliquots of each plasma sample were analyzed. The total radioactivity and thin-layer chromatographic assays used permitted quantitation of tolmetin, its dicarboxylic acid metabolite, and (by difference) all other metabolites collectively for each sample. Time-course data on plasma levels were obtained for individual rats and mice. The plasma elimination half-life of tolmetin was estimated at 0.67 +/- 0.13 hr (mean +/- SD) in male rats, 1.4 +/- 0.6 hr in female rats, 1.2 +/- 0.3 hr in male mice, and 1.0 +/- 0.0 hr in female mice. A one-compartment open model was used.