Absorption, distribution, metabolism and excretion of the cholecystokinin-1 antagonist dexloxiglumide in the dog.

Single oral doses of 14C-dexloxiglumide were rapidly and extensively absorbed in dogs and also eliminated rapidly with a short half-life. Following single intravenous doses, dexloxiglumide was characterised as a drug having a high clearance (30.7 and 27.0 ml/min/kg in males and females respectively), a low volume of distribution (Vss, 0.34 and 0.27 L/kg in males and females respectively) and a moderate systemic availability (about 33%). It was extensively bound to plasma proteins (89%). Dexloxiglumide is mainly cleared by the liver. Its renal clearance was minor. In only the kidney, liver and gastrointestinal tract, were concentrations of 14C generally greater than those in plasma. 14C concentrations generally peaked at 0.25h and declined rapidly during 24h being present only in a few tissues (such as the kidney, liver and gastrointestinal tract) at 24h. Single intravenous or oral doses were mainly excreted in the faeces (77-89%), mostly during 24h. Urine contained up to 7.5% dose. Mean recoveries during 7 days ranged between 93-97%. Biliary excretion of 14C was prominent (64% dose during 24h) in the disposition of 14C which was probably also subjected to some limited enterohepatic circulation. Unchanged dexloxiglumide was the major component in plasma. Urine and faeces contained several 14C-components amongst which unchanged dexloxiglumide was the most important (eg. about 55% dose in faeces). LC-MS/MS of urine and bile extracts showed that dexloxiglumide was metabolised mainly by O-demethylation and by conjugation with glucuronic acid.

Absorption, distribution, metabolism and excretion of the cholecystokinin-1 antagonist dexloxiglumide in the rat.

Single oral doses of 14C-dexloxiglumide were rapidly and extensively absorbed in rats, and eliminated more slowly by females than by males. The respective half-lives were about 4.9 and 2.1 h. Following single intravenous doses, dexloxiglumide was characterised as a drug having a low clearance (6.01 and about 1.96 ml/min/kg in males and females respectively), a moderate volume of distribution (Vss, 0.98 and about 1.1 L/kg in males and females respectively) and a high systemic availability. It was extensively bound to plasma proteins (97%). Dexloxiglumide is mainly cleared by the liver. Its renal clearance was minor. In only the liver and gastrointestinal tract, were concentrations of 14C generally greater than those in plasma. Peak 14C concentrations generally occurred at 1-2 h in males and at 2-4 h in females. Tissue 14C concentrations then declined by severalfold during 24 h although still present in most tissues at 24 h but only in a few tissues (such as the liver and gastrointestinal tract) at 168 h. Decline of 14C was less rapid in the tissues of females than in those of males. Single intravenous or oral doses were mainly excreted in the faeces (87-92%), mostly during 24 h and more slowly from females than from males. Urines contained less than 11% dose. Mean recoveries during 7 days when 14C was not detectable in the carcass except in one female rat ranged between 93-101%. Biliary excretion of 14C was prominent (84-91% dose during 24 h) in the disposition of 14C which was also subjected to facile enterohepatic circulation (74% dose). Metabolite profiles in plasma and selected tissues differed. In the former, unchanged dexloxiglumide was the major component whereas in the latter, a polar component was dominant. Urine, bile and faeces contained several 14C-components amongst which unchanged dexloxiglumide was the most important (eg. up to 63% dose in bile). LC-MS/MS showed that dexloxiglumide was metabolised mainly by hydroxylation in the N-(3-methoxypropyl)pentyl sidechain and by O-demethylation followed by subsequent oxidation of the resulting alcohol to a carboxylic acid.

Pharmacokinetics and metabolism of the cholecystokinin antagonist dexloxiglumide in male human subjects.

1. Mean concentrations of total (14)C and of dexloxiglumide at the end of single 20-min infusion doses of (14)C-dexloxiglumide (200 mg) to four healthy male subjects were 18.5 microg eq x ml(-1) and 19.5 microg ml(-1) respectively. The mean plasma clearance (0.22 l h(-1) x kg(-1)) and mean volume of distribution (V(ss) = 0.18 l kg(-1)) were low. 2. Single oral doses of a solid formulation of (14)C-dexloxiglumide (200 mg) to the same subjects appeared to be rapidly and well absorbed. Mean peak plasma concentrations (C(max)) of total (14)C (2.8 microg eq x ml(-1)) and of dexloxiglumide (2.2 microg x ml(-1)) occurred at about 1.5 h. Systemic availabilities of the oral dose based on total (14)C and dexloxiglumide were 70 and 48%, respectively. Thus, a proportion of an oral dose was subjected to presystemic elimination and the absorbed dose mainly eliminated by metabolism. Binding of dexloxiglumide to plasma proteins was extensive (96.6-99.2%). 3. Total (14)C was excreted mainly in the faeces. Mass balance of (14)C excretion was almost complete within 7 days when a mean of > 93% of the dose had been recovered. After the intravenous (i.v.) dose, mean totals of 23.7 and 69.8% of the dose were excreted in urine and faeces, respectively, during 7 days, and 19.5 and 73.7% of the dose, respectively, after the oral dose. The data were consistent with biliary excretion and perhaps some enterohepatic circulation of conjugates of dexloxiglumide and at least one of its metabolites. 4. LC-MS/MS of urine extracts showed that dexloxiglumide was metabolized by oxidation and conjugation. The former included at least two metabolites formed by monohydroxylation in the N-(3-methoxypropyl) pentyl side chain, and O-demethylation of this side chain followed by subsequent oxidation of the resultant alcohol to the dicarboxylic acid. At least one glucuronide was also present in urine. The main components in faeces appeared to be dexloxiglumide and a dicarboxylic metabolite formed by O-demethylation followed by oxidation of the N-(3-methoxypropyl) side chain. Both compounds were identified as their corresponding methyl esters formed because acid and methanol were used in the extraction procedure. Dexloxiglumide and the dicarboxylic acid were presumably excreted in bile as the glucuronic acid conjugates.

Orally active isoxazoline glycoprotein IIb/IIIa antagonists with extended duration of action.

Modification of the alpha-carbamate substituent of isoxazoline GPIIb/IIIa (alphaIIb beta3) antagonist DMP 754 (7) led to a series of alpha-sulfonamide and alpha-sulfamide diaminopropionate isoxazolinylacetamides which were found to be potent inhibitors of in vitro platelet aggregation. Aryl- and heteroaryl-alpha-sulfonamide groups, in conjunction with (5R)-isoxazoline (2S)-diaminopropionate stereochemistry, were found to impart a pronounced duration of antiplatelet effect in dogs, potentially due to high affinity for unactivated platelets. Isoxazolylsulfonamide 34b (DMP 802), a highly selective GPIIb/IIIa antagonist, demonstrated a prolonged duration of action after iv and po dosing and high affinity for resting and activated platelets. The prolonged antiplatelet profile of DMP 802 in dogs and the high affinity of DMP 802 for human platelets may be predictive of clinical utility as a once-daily antiplatelet agent.

Biological matrix-dependent pharmacokinetic and pharmacodynamic parameters of a novel platelet glycoprotein IIB/IIIA receptor antagonist, XU063, in beagle dogs.

The pharmacokinetic-pharmacodynamic (PK/PD) relationship of a novel platelet glycoprotein IIb/IIIa receptor antagonist, XU063, was evaluated as a function of biological matrix in beagle dogs. The disposition of 14C-radioactivity in various blood or plasma matrices and kinetics of inhibition of adenosine diphosphate (ADP) induced platelet aggregation were determined in beagle dogs following an intravenous infusion of 14C-XU063 at 2 micrograms/kg for 45 min. The 14C-radioactivity was maximum in platelet poor plasma (PPP) harvested from blood collected in EDTA and lowest in PPP harvested from blood collected in citrated vacutainers over the entire concentration versus time profile during and post infusion. The 14C-radioactivity values in blood and platelet rich plasma (PRP) were comparable and were between EDTA PPP and citrated PPP values. The resultant estimates of the PK and PD parameters of 14C-XU063 varied widely depending on the type of matrix used. The systemic clearance values for 14C-XU063 were 1 and 10 mL/min/kg for EDTA and citrated PPP, respectively. The values for the volume of distribution at steady-state were 0.2 and 1.3 L/kg, for EDTA and citrated PPP, respectively. The terminal elimination half-life appeared independent of the matrix with a median value of 2 h. The estimated ex vivo IC50 values of XU063 ranged from 0.4 ng/mL (citrated PPP, platelet free drug) to 7 ng/mL (EDTA PPP, total drug). These results demonstrated the dependence of PK and PD parameters of antiplatelet agent XU063 on the type of biological matrix used to determine concentrations of XU063. The pros and cons of various blood sample collection methods for the evaluation of PK/PD relationship of potential antiplatelet agents are presented.

Oral antiplatelet, antithrombotic efficacy of DMP 728, a novel platelet GPIIb/IIIa antagonist.

BACKGROUND: Currently used antiplatelet drugs, including aspirin and ticlopidine, are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. DMP 728 has been characterized as a potent and specific platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa) antagonist. The goals of the present study were to determine the oral antiplatelet and antithrombotic efficacies of DMP 728 in various arterial thrombosis models in dogs. METHODS AND RESULTS: In conscious and anesthetized mongrel dogs, DMP 728 at 0.02 to 1.0 mg/kg PO in gelatin capsules produced dose-dependent antiplatelet effects in inhibiting ex vivo platelet aggregation induced by ADP and prolonging template bleeding time. DMP 728 effects on bleeding time prolongation could be reversed more rapidly than those on platelet aggregation inhibition. A maximal antiplatelet effect for DMP 728 was demonstrated at 1.0 mg/kg PO. DMP 728 demonstrated dose-dependent oral antiplatelet effects with an absolute oral bioavailability of 8% to 12% in dogs. Additionally, the antithrombotic efficacy of DMP 728 was examined after intravenous and oral administration at different doses in various models of arterial thrombosis. In the coronary artery Folts' model in dogs, DMP 728 demonstrated maximal antithrombotic efficacy at 0.01 mg/kg IV and < 0.6 mg/kg PO. Additionally, DMP 728 at 0.1 and 1.0 mg/kg IV or PO demonstrated 60% to 100% prevention of primary thrombosis (P < .01) in an electrolytically induced carotid artery thrombosis model in dogs. CONCLUSIONS: These data suggest that DMP 728, a low-molecular-weight GPIIb/IIIa receptor antagonist, may have therapeutic potential as an oral antithrombotic agent in coronary and carotid artery thromboembolic disorders.

Dose and species dependent pharmacokinetics of a novel sigma receptor antagonist, DuP 734.

The pharmacokinetics of a novel sigma receptor antagonist, DuP 734, was evaluated in mice, rats, beagle dogs and cynomolgus monkeys at various intravenous and oral doses utilizing a specific reversed-phase HPLC assay. Following intravenous dosing, the disposition of DuP 734 in all species was characterized by high total body systemic plasma clearance (46 to 87 ml/min/kg) and large steady-state volume of distribution (3.6 to 6.8 l/kg). The terminal elimination half-life ranged from 50 to 83 min. The gastrointestinal absorption from an aqueous solution was very rapid in mice and rats with peak DuP 734 plasma concentrations attained within 5 and 20 min following administration, respectively. The peak plasma concentrations in dogs and monkeys were attained within 45 and 130 min, respectively. The absolute bioavailability in mice ranged from 29 to 46% at doses of 3.1 to 30.1 mg/kg. The bioavailability increased from 4 to 10% and from 14 to 72% when doses were increased from 12.5 to 50 mg/kg and 1 to 3 mg/kg of DuP 734 in rats and dogs, respectively. The bioavailability in monkeys was 30.5% at 9.3 mg/kg DuP 734 dose. The dose dependent pharmacokinetics of DuP 734 was observed within narrow dose ranges in all animal species investigated.

Determination of a novel cognitive enhancer, X9121, and its mono N-oxide metabolite, XG696, in dog plasma by reversed-phase high-performance liquid chromatography with ultraviolet detection.

A selective and sensitive high-performance liquid chromatographic assay for a novel cognitive enhancer, X9121 (I), and its mono N-oxide metabolite, XG696 (II), in dog plasma has been developed. Compounds I, II and internal standard (I.S.) were first extracted from dog plasma using a solid-phase Bond Elut Certify I 10-ml LRC reservoir extraction cartridge. Chromatographic separation of I, II and I.S. was conducted on a reversed-phase Zorbax Stable Bond cyano column. Ammonium acetate buffer (0.05 M, pH 6)-acetonitrile-triethylamine (75:25:0.1, v/v) was used as the mobile phase. Detection of all three compounds was by UV light absorbance at 313 nm. Using 0.5 ml of dog plasma for extraction, the minimum quantifiable limit was 10 ng/ml and the assay was linear from 10 to 5400 ng/ml. The coefficients of variation for intra-day precision ranged from 2.2 to 8.5% for I and from 2.5 to 9.8% for II. The coefficients of variation for the inter-day precision for these two compounds ranged from 2.6 to 9.0% and from 3.6 to 16.2%, respectively. The absolute percent differences for the accuracy results were within 11.0% of the spiked concentrations. Compounds I and II were stable in frozen plasma at -20 degrees C for at least 67 days.

Determination of DMP 728, a IIb/IIIa receptor antagonist, in rat and dog plasma by high-performance liquid chromatography with fluorimetric detection.

A specific and sensitive HPLC assay for the determination of DMP 728 in dog and rat plasma has been developed. The method involves solid-phase extraction of DMP 728 and the internal standard from plasma using a C2 column. The extracted compounds are derivatized with benzoin under alkaline conditions. Using a mixture of acetonitrile and 0.1 M potassium phosphate buffer (25:75, v/v, pH 7.4) as mobile phase, the derivatized products are separated on a Regis semipermeable surface C8 column and monitored fluorometrically using 325 nm and 425 nm as excitation and emission wavelengths, respectively. The assay is linear from 2.5 to 1000 ng/ml in dog plasma and from 5 to 1000 ng/ml in rat plasma. The limit of quantitation is 2.5 ng/ml using 0.5 ml of dog plasma and 5 ng/ml using 0.5 ml of rat plasma. The assay has been used in pharmacokinetic studies of DMP 728 in dogs and rats.

Determination of a novel sigma receptor antagonist, DuP 734, in rat plasma by reversed-phase high-performance liquid chromatography with ultraviolet detection.

A selective high-performance liquid chromatographic (HPLC) assay for a sigma receptor antagonist, DuP 734 (I), in rat plasma has been developed. Compound I and internal standard, XC031 (I.S.), were first extracted from plasma into an ethyl acetate-toluene mixture (3:7, v/v) and then back-extracted into freshly prepared phosphoric acid (0.03 M). Separation of I and I.S. with no interference from endogenous substances was achieved on a reversed-phase octyl column and detection was by UV at 229 nm. The mobile phase consisted of acetonitrile-glacial acetic acid-triethylamine-0.05 M ammonium acetate (670:4:2:2000, v/v). Using 0.5 ml of rat plasma for extraction, the limit of quantitation was 43 ng/ml and the assay was linear from 43 to 8536 ng/ml. The intra- and inter-day coefficients of variation ranged from 0.7 to 3.0%, and from 1.4 to 14.5%, respectively, over the entire concentration range. The accuracy was within 16.1% of the spiked concentrations. I was stable in frozen plasma at -20 degrees C for at least 68 days.

Antiplatelet and antithrombotic efficacy of DMP 728, a novel platelet GPIIb/IIIa receptor antagonist.

BACKGROUND: Currently used antiplatelet drugs, including aspirin, ticlopidine, and others, are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. Thus, we have identified a systemically active peptide analogue (DMP 728) of the arginine-glycine-aspartic acid (RGD) recognition sequence that mediates the binding of ligands such as fibrinogen to the platelet glycoprotein (GP) IIb/IIIa receptors. The goals of the present study were to determine the antiplatelet and antithrombotic efficacies of DMP 728 in various arterial thrombosis models. METHODS AND RESULTS: DMP 728 demonstrated antiplatelet efficacy in vitro in inhibiting ADP-induced human platelet aggregation (IC50, 46 +/- 2 nmol/L) and fibrinogen binding to human platelets (IC50, 2.3 +/- 0.8 nmol/L) or purified human GPIIb/IIIa receptors (IC50, 0.6 +/- 0.1 nmol/L). DMP 728 demonstrated high affinity and specificity for human platelet GPIIb/IIIa over other adhesion molecules. In anesthetized mongrel dogs, DMP 728 at 0.001 to 1.0 mg/kg IV produced dose-dependent antiplatelet effects in inhibiting ex vivo platelet aggregation induced by ADP and in prolonging template bleeding time. DMP 728 effects on bleeding time prolongation were more rapidly reversible than those on platelet aggregation inhibition. A maximal antiplatelet effect for DMP 728 was demonstrated at 0.01 mg/kg IV bolus. The antithrombotic efficacy of DMP 728 was examined in vitro and in vivo after IV administration at different doses in various models of arterial thrombosis. In the coronary artery Folts model in dogs, DMP 728 demonstrated maximal antithrombotic efficacy at 0.01 mg/kg IV bolus with an ED50 of 0.005 mg/kg IV bolus in inhibiting cyclic flow reductions. Additionally, DMP 728 demonstrated 100% prevention of primary thrombosis and rethrombosis (P < .01) after treatment with different thrombolytics, including tissue plasminogen activator and streptokinase, in an electrolytically induced femoral artery thrombosis model in dogs. CONCLUSIONS: Acute intravenous DMP 728 administration (0.001 to 1.0 mg/kg) has dose-dependent antiplatelet and antithrombotic effects in different arterial thrombosis models. These data suggest that DMP 728, a low-molecular-weight GPIIb/IIIa receptor antagonist, may have therapeutic potential as an effective antithrombotic agent in coronary and peripheral artery thromboembolic disorders.

Nanogram level quantitation of oxycodone in human plasma by capillary gas chromatography using nitrogen-phosphorus selective detection.

A sensitive and specific capillary gas chromatographic assay is reported for the quantitation of oxycodone in human plasma. The technique involves a single extraction of oxycodone and internal standard (hydrocodone) from plasma by toluene containing 1% isopropanol. Separation is achieved on a methyl silicone (HP-1) fused-silica capillary column (25 m x 0.2 mm I.D., 0.33 microns film thickness) and detection is by nitrogen-phosphorus selective mode. The minimum quantifiable limit is 1.8 ng/ml using 2 ml of plasma. The method is applicable to characterize the plasma profile of oxycodone in humans after a single oral 5-mg oxycodone hydrochloride tablet.

Cardioteratogenic dose of ethanol in the chick embryo results in egg white concentrations comparable to human blood alcohol levels.

Three-day-old chick embryos were exposed to a dose of ethyl alcohol (0.32 ml of 50% ethanol) that we previously demonstrated produces cardiac malformations in 96.6% of the animals. Ethanol was administered into the air sac at 72-80 h of incubation. Samples of egg white were drawn at 2, 6 and 24 h after treatment and analyzed by capillary gas-liquid chromatography. Ethanol concentrations were significantly higher at 6 and 24 h after exposure than at 2 h (P less than 0.01), but there were no differences in mean concentrations between 6 and 24 h (P greater than 0.2). Furthermore, concentrations (43-303 mg dl-1) were comparable to human blood alcohol levels during intoxication. These results suggest that the cardioteratogenic doses of ethanol administered to chick embryos in a previous study are not excessive in terms of potential human embryo exposure.

The effect of histamine-2 receptor antagonists on tocainide pharmacokinetics.

The effects of cimetidine and ranitidine on tocainide pharmacokinetics were assessed in seven healthy subjects, using a randomized, double-blind, placebo-controlled, cross-over study design. After a 400-mg oral dose of tocainide, the area under the concentration-time curve decreased from (mean +/- SD) 31.64 +/- 14.16 micrograms.hr/mL during placebo, to 23.10 +/- 7.33 micrograms.hr/mL during cimetidine (P less than .05). Similarly, the peak tocainide concentrations were 2.81 +/- 0.89 micrograms/mL and 1.70 +/- 0.44 micrograms/mL with placebo and cimetidine, respectively (P less than .05). There was no change in the above parameters between ranitidine and placebo. The terminal half-life and renal clearance of tocainide were not altered by either H2-receptor antagonists, compared with placebo. However, the total amount of tocainide excreted unchanged in the urine, decreased from 159.8 +/- 14.7 mg with placebo to 136.8 +/- 26.8 mg with cimetidine (P less than .05), whereas there was no change with ranitidine. These data indicate that cimetidine, but not ranitidine, causes a decrease in the bioavailability of tocainide and that neither agent alters the apparent elimination rate of tocainide.

Disopyramide pharmacokinetics and metabolism: effect of inducers.

1. The disposition of orally administered disopyramide was studied in a population of smokers (n = 6) and non-smokers (n = 8) before and during phenobarbitone treatment (100 mg daily for 21 days; Cp 21st day = 13.9 +/- 2.0 micrograms ml-1). The comparative inducibility of these populations by phenobarbitone was assessed as was the inductive effect of cigarette smoking, per se. Furthermore, the determinants of the intensity of the inductive effect were examined, as well as the effect of the barbiturate on the binding of disopyramide to alpha 1-acid glycoprotein (AGP). 2. Smokers and non-smokers exhibited similar half-lives (6.48 +/- 1.49 vs 6.66 +/- 1.02 h), apparent total body clearances (0.100 +/- 0.020 vs 0.117 +/- 0.034 l h-1 kg-1), mean renal clearances (0.043 +/- 0.0093 vs 0.057 +/- 0.013 l h-1 kg-1) and apparent intrinsic metabolic clearances (0.057 +/- 0.015 vs 0.060 +/- 0.024 l h-1 kg-1) before phenobarbitone treatment. 3. Both populations responded comparably to barbiturate exposure in that apparent intrinsic metabolic clearance more than doubled. Interestingly, the magnitude of this increase was highly dependent on the observed baseline apparent intrinsic metabolic clearance, (r' = 0.81; P less than 0.001). 4. Phenobarbitone treatment of non-smokers resulted in an increase in the AUC of the active metabolite N-despropyl disopyramide (MND), but not significantly (3.8 +/- 1.6 vs 4.1 +/- 2.3 micrograms ml-1 h). Similar results were observed in smokers (3.5 +/- 1.4 vs 3.9 +/- 2.0 micrograms ml-1 h, respectively). 5. The percent of administered dose recovered in urine as disopyramide in non-smokers was significantly decreased upon phenobarbitone treatment (43 +/- 6% vs 25 +/- 5%), whereas the percent of dose recovered as MND increased significantly in this group (25 +/- 6% vs 31 +/- 5%). The population of smokers responded similarly. 6. At doses typically used to achieve hepatic microsomal enzyme induction in man, phenobarbitone treatment caused no significant change or trend towards a change in serum AGP concentrations as measured using the radial immunodiffusion method in nonsmokers (67.4 +/- 19.9 mg dl-1 vs 68.0 +/- 40.7 mg dl-1) or smokers (64.5 +/- 15.7 vs 67.9 +/- 14.9). Similarly, when AGP concentration was estimated in serum from non-smokers using a nephelometric method no effect attributable to phenobarbitone was observed (47.9 +/- 1.3 vs 47.9 +/- 16.8 mg dl-1). Consistent with this observation, disopyramide free fraction was not affected by barbiturate treatment.

Applicability of capillary gas liquid chromatography to the measurement of free fraction of disopyramide in human plasma.

A sensitive and specific capillary gas liquid chromatographic nitrogen/phosphorus selective detection technique was used to measure unbound disopyramide in human plasma. The concentration dependent protein binding of disopyramide was examined. Various concentrations of disopyramide alone ranging from 0.5 to 10.0 micrograms/ml in 0.4 ml of isotonic phosphate buffer (pH 7.4) were dialyzed for 6 hours at 37 degrees C, against 0.4 ml blank plasma from five healthy volunteers. The concentration-dependent binding of disopyramide was confirmed. The average free fraction for disopyramide at concentrations of 0.5, 1.0, 2.0, 3.0, 4.0, 5.0 and 10.0 micrograms/ml were 0.14, 0.15, 0.20, 0.27, 0.30, 0.34 and 0.53, respectively.

Simultaneous quantitation of disopyramide and its mono-dealkylated metabolite in human plasma by fused-silica capillary gas chromatography using nitrogen-phosphorus specific detection.

A nitrogen-specific detector gas-liquid chromatographic assay method is reported which provides improved selectivity and sensitivity for disopyramide and its mono-N-dealkylated metabolite using a crosslinked fused-silica capillary column. The quantitation of disopyramide and mono-N-dealkylated disopyramide was accomplished by injecting trifluoroacetic anhydride-treated samples containing derivatized internal standard p- chlorodisopyramide , into a gas chromatograph equipped with a nitrogen--phosphorus detector and an automatic liquid sampler. A 25 m X 0.31 mm crosslinked, 5% phenylmethyl silicone-coated fused-silica column was utilized and samples were injected using the splitless injection mode. Linearity was observed in the range 0.05-5.00 micrograms/ml for disopyramide and 0.02-3.00 micrograms/ml for the mono-N-dealkylated metabolite. The coefficient of variation was found to be within 10% for both compounds in the concentration range studied.

Nonlinear bioavailability of metoclopramide in the rat: evidence for saturable first-pass metabolism.

In vivo and in vitro experiments were conducted in rats to examine the possibility of either extrahepatic metabolism or saturable first-pass effect as an explanation for the unusual presystemic clearance of metoclopramide (I) previously reported. In vivo studies involved two-thirds hepatectomized rats and animals pretreated with carbon tetrachloride to induce hepatic necrosis, whereas in vitro studies involved incubation of equal amounts of I (5.0 mumol/mL) with various tissue homogenates (viz., liver, kidney, and lung) or their 9000 X g supernatant fractions. Results suggest that the metabolism of I principally occurs in the rat liver, and there was no evidence suggesting the involvement of kidney or lung tissue in the metabolism of I. Forty-eight-hour cumulative urinary excretion studies following oral and intravenous administration of less than or equal to 5.0 mg/kg of metoclopramide hydrochloride were conducted. The bioavailability (F) values of I at dosage levels 0.1, 0.5, 1.0, and 5.0 mg/kg were 0.49, 0.75, 0.77, and 0.83, respectively. It is concluded that the liver is the primary organ for the metabolism of I in the rat and that the drug exhibits dose-dependent hepatic first-pass metabolism.