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S Vickers

Publications and source records attributed to S Vickers.

46 records · Page 3Linked to original sources
PubMedDate not supplied

In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG CoA reductase.

Simvastatin (SV), an analog of lovastatin, is the lactone form of 1', 2', 6', 7', 8', 8a'-hexahydro-3,5-dihydroxy-2', 6'-dimethyl-8' (2", 2"-dimethyl-1"-oxobutoxy)-1'-naphthalene-heptanoic acid (SVA) which lowers plasma cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase. SV but not its corresponding hydroxy acid form SVA underwent microsomal metabolism. Major in vitro metabolites were 6'-OH-SV (I) and 3"-OH-SV (III) formed by allylic and aliphatic hydroxylation, respectively, and 6'-exomethylene-SV (IV) formed by dehydrogenation. In rats, dogs, and humans, biliary excretion is the major route of elimination. Biliary metabolites (as both hydroxy acids and lactones) also included 6'-CH2OH-SV (V) and 6'-COOH-SV (VI) in both of which the 6'-chiral center had been inverted. High levels of esterase in rodent plasma favored the formation of SVA from SV. The formation of 1', 2', 6', 7', 8', 8a'-hexahydro-2', 6'-dimethyl-8'-(2",2"-dimethyl-1-oxobutoxy)-1'-naphthalene-pentano ic acid (VII) only in rodents represented a species difference in the metabolism of SV. It is proposed that VII is formed by beta-oxidation pathways of fatty acid intermediary metabolism. Several metabolites resulting from microsomal oxidation (after subsequent conversion from lactones to hydroxy acids) are effective inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase and may contribute to the cholesterol lowering effect of SV. Qualitatively, the metabolism of SV closely resembles that of lovastatin.

Aged↗
PubMedDate not supplied

The physiological disposition of lovastatin.

Lovastatin is a pro-drug lactone whose open chain beta-hydroxy-acid (HA) is a potent inhibitor of hydroxymethylglutaryl-CoA-reductase and thus of cholesterol synthesis. Because the liver is the major site of cholesterolgenesis, it is the principal target organ for agents of this class. In animals, lovastatin is not as well absorbed as HA given per se, but that fraction that is absorbed reaches the portal circulation largely unchanged and is more efficiently extracted by the liver, after which it is reversibly biotransformed to HA and irreversibly to other enzymatically active products. These, like HA, maintain high hepatic gradients relative to all tissues examined. The minimal systemic burden for HA is attributable in part to the metabolic equilibrium, lovastatin in equilibrium HA, the opposing reactions for which appear to be present in most tissues. Excretion is very largely biliary in all species. Detailed comparisons of absorption, distribution, metabolism, and excretion profiles presented here and elsewhere indicate dogs to be the most appropriate paradigm for humans for study of lovastatin disposition.

Animals↗
PubMedDate not supplied

Evaluation of succinimidoethyl and pivaloyloxyethyl esters as progenitors of methyldopa in man, rhesus monkey, dog, and rat.

The succinimidoethyl (Sm) and pivaloyloxyethyl (P) esters of methyldopa were evaluated as progenitors of the latter. Experiments in spontaneously hypertensive (SH) rats and humans demonstrated that a radioactive dose of progenitor was well absorbed. The metabolism of these progenitors appeared to be comparable in the SH rat; the urinary excretion of [3H]methyldopa was similar after oral administration of [3H]Sm or [3H]P. In humans the levels of [3H]methyldopa were higher in the urine following administration of [3H]P. Apparently Sm was more resistant than P to extrahepatic esterase action in man (and dog). In man the catechol nucleus of Sm was apparently conjugated prior to hydrolytic cleavage to release conjugated [3H]methyidopa. The progenitors possessed similar antihypertensive properties in the SH rat but preliminary results in humans suggested that Sm possessed less antihypertensive potency than P.

Adult↗
PubMedDate not supplied

The metabolic disposition of (S)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-cyanopyridine in rats, dogs, and humans.

Studies of the metabolic disposition of (S)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-[14C]cyanopyridine (I) have been performed in humans, dogs, and spontaneously hypertensive rats. After an iv injection of I (5 mg/kg), a substantial fraction of the radioactivity was excreted in the feces of rats (32%) and dogs (31%). After oral administration of I (5 mg/kg) the urinary recoveries of radioactivity for rat and dog were 19% and 53%, respectively, and represented a minimum value for absorption because of biliary excretion of radioactivity. In man, bililary excretion of I appeared to be of minor significance because four male subjects, after receiving 6 mg of I p.o., excreted 76% and 9% of the dose of radioactivity in the urine and feces, respectively. Unchanged I represented 58% of the radioactivity excreted in human urine. The half-life for renal elimination of I was determined to be 4.0 +/- 0.9 /hr. In contrast, unchanged I represented 7% and 1% of excreted radioactivity in rat and dog urine, respectively. A metabolite of I common to man, dog, and rat was identified as 5-hydroxy-I, which represented approximately 5% of the excreted radioactivity in all species. Minor metabolites of I in which the pyridine nucleus had undergone additional hydroxylation were present in dog urine along with an oxyacetic acid metabolite, also bearing a hydroxylated pyridine nucleus.

Animals↗
PubMedDate not supplied

Metabolism of the TRH analog L-pyro-2-aminoadipyl-L-histidyl-[3H]-L-thiazolidine-4-carboxamide (MK-771) in gut and brain tissue of rats: the implications for its bioavailability.

Hydrolysis of the terminal amide group of L-pyro-2-aminoadipyl-L-histidyl-[3H]-L-thiazolidine-4-carboxamide ([3H]MK-771) in rat brain homogenates was rapid and yielded the corresponding [3H] tripeptide carboxylic acid (III). Brain proteolytic enzymes may limit the bioavailability of [3H]MK-771. In contrast MK-771 degradation in a rat gut homogenate (where the radiolabeled product of hydrolysis was [3H]thioproline) was much slower and intestinal proteolytic enzymes probably did not prevent the absorption of MK-771 into the systemic circulation. However, the majority of an oral dose of MK-771 was not absorbed and intact MK-771 represented only 2% of the fecal radioactivity. Degradation of unabsorbed MK-771 occurred mainly in the large intestine of normal rats presumably because of the action of gut flora. Eighty percent of the oral dose remained in the intestine of germ-free rats as intact MK-771 and it was concluded that the limited absorption of MK-771 was caused by its inefficient transportation across gut membranes.

Animals↗
PubMedDate not supplied

Metabolism of methyldopa in man after oral administration of the pivaloyloxyethyl ester.

In a crossover study, the pivaloyloxyethyl ester (POE) of methyldopa, labeled either with 3H in the methyldopa moiety or 14C in the pivalic acid moiety, was administered orally to four volunteers in 1000-mg single doses (equivalent to 500 mg of methyldopa). The majority (93%) of either the 3H- or 14C-labeled dose was excreted in the urine. Methyldopa, which was assayed by a fluorometric technique, peaked (approximately 6 micrograms/ml) at 1 hr in the plasma. Forty-five per cent of the dose was excreted as methyldopa as opposed to 18% normally seen after oral methyldopa dosages. Intact POE was absent in the urine of three volunteers and present in only trace amounts in urine from a fourth volunteer. Thus, the oral dose of POE was well absorbed and rapidly hydrolyzed to methyldopa. After oral administration of methyldopa, methyldopa sulfate is the principal urinary metabolite in man. However, after administration of POE, a relatively small fraction (13%) of the dose was excreted as methyldopa sulfate. The major urinary metabolite of POE, other than methyldopa, was 3-OCH3 methyldopa. Methyldopamine was a minor metabolite. It was concluded that a shift from sulfation to methylation occurred in the metabolic profile of methyldopa when it was administered as POE and that the metabolites of POE (including conjugated pivalic acid) were rapidly eliminated from the body.

Administration, Oral↗
PubMedDate not supplied

Disposition of MK-852, a fibrinogen receptor antagonist, in rats and dogs.

MK-852, an antagonist of the platelet fibrinogen receptor GPIIb/IIIa, is the cyclic disulfide N-acetyl-cys-asn-(5,5-dimethyl-4-thiazolidine-carbonyl)- (4-aminomethyl-phe)-gly-asp-cys, monoacetate (all L-amino acids). Radiolabeled MK-852 was synthesized with either a 3H label in the N-acetyl group of the cystine residue or a 14C label in the aminomethyl group. Plasma concentrations of unchanged MK-852 in five rats declined with a mean terminal half-life of 0.92 hr after a 2.5 mg/kg i.v. dose of MK-852; plasma clearance and Vd were 23.1 ml/min/kg and 1.81 liters/kg, respectively. More label was excreted in urine (74-76%) than in feces (7-15%) when either [3H]MK-852 or [14C]MK-852 was given intravenously to groups of four rats (2.5 mg/kg). High concentrations of 3H in rat kidney were consistent with high renal clearance of MK-852, and MK-852 accounted for virtually all of the urinary 3H (and 14C) label. Following a 0.6 mg/kg i.v. dose, the half-life, plasma clearance, and Vd of MK-852 in four dogs were 0.84 hr, 3.93 ml/min/kg, and 0.28 liters/kg, respectively. In dogs, the excretion patterns of radioactivity were similar to those of rats, except that 14C urinary recoveries (79%) were higher than 3H (63%). Unchanged MK-852 represented essentially all of the urinary 3H label. Fractionation of dog 14C urinary radioactivity yielded one major and several minor polar labeled species. The major species was unchanged [14C]MK-852 (quantitated by radioimmunoassay as approximately 80% of the label).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMedDate not supplied

In vivo and in vitro metabolism studies on a class III antiarrhythmic agent.

The metabolism of L-691,121 (I), a class III antiarrhythmic agent, was studied in vivo in rats and dogs and in vitro by using liver S9 or slices from these species and humans. After oral doses of [14C]I to rats (5 mg/kg) and dogs (1 mg/kg), urinary recoveries of label were, respectively, 6% and 28%. Biliary excretion (0-24 hr) accounted for 68% of a 5 mg/kg, po dose in rats and 19% of a 10 mg/kg dose, po in dogs. Metabolites were identified by application of FAB/MS, NMR, and diode-array UV spectroscopy. The major dog metabolites were the secondary alcohol (II) produced by carbonyl reduction and its glucuronide conjugate (III). It was estimated that II and III represented 24 and 36%, respectively, of the dog biliary radioactivity. After a 50 mg/kg dose of I, II represented approximately 50% of the dog urinary label. A minor metabolite (IV) in dog urine was produced by reduction and loss of N-substitution. There were species differences in that, relative to dogs, II represented a much smaller fraction of the excreted dose in rats and there was no evidence for excretion of III in rats. N-Dealkylated I (V) was excreted, along with IV in rat bile. Dog liver slices and S9 fractions were most efficient (relative to human and rat liver tissues) at reducing I to II. Metabolic reduction of I to II was highly stereoselective and yielded the (-)-antipode as determined by chiral chromatography.

Aged↗
PubMedDate not supplied

Metabolic disposition of simvastatin in patients with T-tube drainage.

A study to investigate the disposition and biliary excretion of simvastatin (SV) was conducted in four cholecystectomy patients with T-tube drainage. Each patient received a single oral dose of 100 mg of [14C]SV (20 microCi). Of the 14C-labeled dose, approximately 35% was excreted in urine, 25% in bile, and 20% in feces. Thus, at least 60% of the oral dose was absorbed from the gastrointestinal tract. Of the AUC for radioactivity in plasma, 13% was contributed by the HMG-CoA reductase inhibitors. In addition, only 2% of the 14C-dose was eliminated in urine as HMG-CoA reductase inhibitors. Thus, most of the SV-related compounds in plasma and urine have little or no HMG-CoA reductase inhibitory activity. The same is probably true for these compounds in bile. Two major active metabolites were present in the bile. Based on HPLC and MS/MS data, they were identified as 6' beta-COOH-SVA and 6'-OH-SVA. In general, the majority of the radioactivity in the bile and urine was excreted within 24 hr postdose. Of the radioactivity excreted in the 0- to 24-hr bile, on average, approximately 30% was contributed by 6' beta-COOH-SVA and 6'-OH-SVA. These two metabolites accounted for the majority of HMG-CoA reductase inhibitory activity in the bile. Little or SV or no SVA was present in the bile.

Adult↗