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K S Pang

Publications and source records attributed to K S Pang.

At least 127 records · Page 7Linked to original sources
PubMed1978

Kinetics of metabolite formation and elimination in the perfused rat liver preparation: differences between the elimination of preformed acetaminophen and acetaminophen formed from phenacetin.

Both [14C]phenacetin and [3H]acetaminophen in tracer concentrations were perfused simultaneously once through the rat liver preparation at a constant perfusate flow rate (10 ml/min), and the rates of appearance of [14C]acetaminophen and [3H]acetaminophen in the effluent were compared. The data indicated that the extraction ratio of [14C]acetaminophen derived from [14C]phenacetin was smaller than that of the preformed [3H]acetaminophen added to the input perfusate (exogenously), i.e., the availability of the metabolite formed in situ was higher than the availability obtained when the metabolite was presented in the input blood. The observed availability of the acetaminophen derived from phenacetin was usually greater than that predicted by a "well-stirred" model and less than that predicted by a "parallel tube" model of hepatic drug clearance; the former model describes the liver as a well-stirred compartment with the drug in liver in equilibrium with that in the hepatic venous blood, and the latter model describes the liver as a group of identical and parallel uints with enzymes distributed evenly in hepatocytes lining the tubes. We conclude that the liver may be viewed as an imperfectly mixed compartment with regard to the availability of the metabolite which is generated from a precursor.

Acetaminophen↗
PubMedDate not supplied

Interpretation and estimates of mean residence time with statistical moment theory.

The definitions of mean residence time of drug molecules in the body (MRT) from the literature are reviewed. A formal definition of MRT, based on excretion of drug molecules and amount of drug, a parameter which is independent of constancy of both clearance and volume of distribution, is introduced and compared to other existing definitions of MRTs, that is, MRT for the two-compartment model, MRT for the stochastic model, and MRT based on amount in the body. The inherent assumptions of the methods for determining the various MRTs are discussed. Published information on coefficients and constants (Collier) which describe a biexponential drug decay in the systemic circulation were utilized to illustrate the similarities and differences in MRTs. MRTs were calculated from theoretical relationships as well as estimated from simulated data based on equivalent conditions. The MRTs based on area under the moment curve/area under the curve (AUMC/AUC) for the two-compartment model and AUC/C(0) for the stochastic model assume a constancy in clearance and in volume of distribution, respectively.

Absorption↗
PubMedDate not supplied

First-pass metabolism of gentisamide: influence of intestinal metabolism on hepatic formation of conjugates. Studies in the once-through vascularly perfused rat intestine-liver preparation.

Gentisamide (GAM) metabolism was studied in a once-through in situ perfused rat intestine-liver preparation in a manner which mimicked the first-pass effect. GAM (2.56 to 392 microM) was delivered into the intestine via the superior mesenteric artery at a flow of 7.5 ml/min. The intestinal venous outflow into the portal vein and the hepatic arterial flow (2.5 ml/min; without drug) served as dual inflows into the liver. The steady state intestinal extraction ratios (E1, 0.33 to 0.06) and hepatic extraction ratios (EH, 0.84 to 0.37) were highly concentration dependent, decreasing with increasing GAM concentrations. Gentisamide-5-glucuronide was found to be the major intestinal metabolite, and gentisamide-2-sulfate was also formed, albeit to a much lesser extent. However, hepatic metabolism of GAM revealed 5-sulfation and glucuronidation as the predominant pathways, with GAM 2-sulfation as a minor pathway. About 1 to 3% and 7% of dose was excreted into lumen and bile, respectively, mostly as GAM-5G. From the metabolic data, the fitted parameters confirmed that more enzymes exist in the liver than in intestine for the processing of GAM. The Km for 2-sulfation by the intestine was higher than the apparent Kms observed for 2- and 5-sulfation in liver. However, the Kms for 5-glucuronidation for both the intestine and liver were similar. The interrelationship between intestine and liver formation of first-pass metabolites showed that, at low GAM input concentration entering the IL preparation, the intestine, being the anterior organ, regulated the available substrate for hepatic elimination, and hence reduced the contribution of hepatic metabolism in the overall first-pass effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Estimations of intestinal and liver first-pass metabolism in vivo. Studies on gentisamide conjugation in the rat.

In this paper a method is introduced to study both intestinal and liver metabolism in the intact rat by cannulation of the jugular vein, carotid artery, pyloric vein (into the portal vein), and bladder. In this preparation, the rat received an initial dose followed by iv (I) and then intraportal (II) infusions. Gentisamide (2,5-dihydroxybenzamide, GAM) was used since it forms monosulfate (GAM-2S and GAM-5S) and monoglucuronide (GAM-5G) conjugates, metabolites that are not further metabolized. After administration of tracer amounts of radiolabeled gentisamide ([3H]GAM), the concentration ratio of [3H]GAM in the portal vein and carotid artery [CPV(I)/CA(I)] during iv infusion, and the ratio of carotid artery concentrations for intraportal to iv infusions [CA(II)/CA(I)] provided the intestine and liver availabilities, respectively; the corresponding extraction ratios for the intestine and liver were 0.26 to 0.27 and 0.37 to 0.41. Similar concentration ratios for the conjugates during iv administration [CPV(I)/CA(I)] showed intestine formation of GAM-5G, and to a lesser extent, GAM-2S, since the ratios exceeded unity; GAM-5S was not formed by the intestine since the ratio was unchanged. The ratio of the carotid arterial concentrations for intraportal to iv infusions that revealed hepatic formation showed similar values (1.77 and 1.71) for GAM-2S and GAM-5S, but variable (decreases and increases) GAM-5G values, whose mean value approximated unity. All findings were consistent with data obtained from the perfused rat liver preparation and the combined perfusion of rat intestine-liver preparation, where GAM-5G and GAM-2S were shown to be formed by the intestine, and where sulfation was the preferred pathway in the liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

First-pass metabolism of salicylamide. Studies in the once-through vascularly perfused rat intestine-liver preparation.

Salicylamide (SAM) metabolism was studied in a once-through in situ perfused rat intestine-liver preparation in a manner which mimicked the first-pass effect. SAM (40 or 200 microM) was delivered into the intestine via the superior mesenteric artery at a flow rate of 7.5 ml/min. The intestine venous outflow into the portal vein and the hepatic arterial flow (2.5 ml/min; without drug) served as dual inflows into the liver. The steady state intestinal and hepatic extraction ratios were 0.262 +/- 0.055 and 0.992 +/- 0.014, respectively, at 40 microM, and 0.206 +/- 0.035 and 0.638 +/- 0.117, respectively, at 200 microM. SAM glucuronide was found to be the only metabolite formed by the intestine at both doses. Less than 3% of the dose was secreted into the intestinal lumen, with SAM glucuronide and SAM as the major and minor components, respectively. Hepatic metabolism of SAM, however, revealed SAM sulfation as the predominant pathway, while glucuronidation and hydroxylation were minor metabolic pathways. About 6% of the dose was excreted into bile, mostly as SAM and gentisamide glucuronides. The interrelationship between the intestine and liver clearances was also examined by mass balance considerations and simulation of data. The total rate of elimination of substrate across the two organs is the sum of the rates of metabolism by each organ. However, the overall effective extraction ratio and, hence, the clearance, are less than the sum of the individual extraction ratios and organ clearances, respectively. Our results showed that intestinal metabolism regulated the available substrate for hepatic elimination, and hence modified the contribution of hepatic metabolism in the overall first-pass effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Metabolism of acetaminophen and phenacetin by isolated rat hepatocytes. A system in which the spatial organization inherent in the liver is disrupted.

The kinetics of sulfation of 3H-acetaminophen (preformed metabolite) and 14C-acetaminophen (generated metabolite) during the parallel incubations of tracer concentrations of 3H-acetaminophen and 14C-phenacetin in (a) isolated rat hepatocytes and (b) rat 9000g supernatant fractions from liver and from isolated hepatocytes were compared to results obtained from rat liver perfusion studies (Pang and Gillette, J. Pharmacol. Exp. Ther. 207, 178-194, 1978; Pang and Terrell, J. Pharmacol. Exp. Ther. 216, 339-346, 1981). The isolated rat hepatocytes and the subcellular fractions represent in vitro systems whose metabolic activities are apparently homogeneous and contrast the in situ rat liver perfusion system where differential distribution of drug metabolizing activities exists within the rigid architecture of the intact organ. The ratio of sulfation (intrinsic clearance = 23.8 ml/min/liver) to O-deethylation (intrinsic clearance = 11.7 ml/min/liver) activities within these isolated hepatocytes (2.2-2.7) and subcellular fractions (3.72) were similar, but were reversed in the perfused liver preparation (0.2-0.5) depending on the model of hepatic drug clearance used for the calculation. Moreover, the sulfation to O-deethylation activity in the isolated rat hepatocyte system was independent of cell concentration (3.8 to 11 X 10(8) cells/ml) or the method of isolation of hepatocytes (by normal digestion or retrograde digestion). The reason for the reversal of lower O-deethylation activity in the subcellular and cellular systems remains unknown.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMedDate not supplied

Absorption and metabolism of acetaminophen by the in situ perfused rat small intestine preparation.

The in situ perfused rat small intestine preparation was used to examine the extents of segmental absorption and metabolism of acetaminophen (A). Additionally, the preparation was employed to investigate any intestinal excretion of A and its conjugates from the circulation to the intestinal lumen. In this preparation, blood perfusate (300 ml) recirculated the intestinal preparation at 7.5 ml/min, entering via the superior mesenteric artery and returned to the reservoir via the portal vein. To demonstrate the extent of segmental absorption, metabolism, and excretion by different segments of the intestine, tracer doses of 3H-A (0.41 to 0.55 mumol in 0.3 ml of saline) were administered into the (a) entire intestine; (b) segments (first, second, and third) of one-third the length of the intestine, by instillation of the dose into the lumens of the segments; and (c) reservoir of perfusate. Exudates of luminal fluid from the injected segment and segments not exposed to drug were monitored for A and its conjugates during the experiment and at the end of 2 hr. Absorption of A was usually complete by 60 min; the extent of absorption of A at the end of 2 hr by the entire length of the intestine and by its three (first, second, and third) individual segments were 71.7 +/- 2.6, 50.5 +/- 4.0, 73.9 +/- 2.1, and 58.8 +/- 6.1% of dose (mean +/- SE), respectively. At the end of 2 hr, the total amount of acetaminophen glucuronide in perfusate and luminal fluid accounted for 3.1-5.5% and 0.14-0.1% of dose, respectively, among these preparations; acetaminophen sulfate was present only as a small percentage of dose in the lumen. Glucuronidation activity, when expressed as a percentage of the absorbed dose, was fairly constant for the entire intestine and first and second segments (8%) but decreased slightly for the third segment (7%). When A was present in blood perfusing the intestine, no metabolite was detected in perfusate or luminal fluid. Instead, unchanged A was excreted (5.6% dose) into the lumen. The effect of dose and vehicle on the extents of absorption and metabolism of A in the preparation was investigated by the instillation of different doses of A (0.16, 99.2, and 396.9 mumol in 0.3 ml of polyethene glycol 400) into the entire intestine at the duodenum.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetaminophen↗
PubMedDate not supplied

Presence of a diffusional barrier on metabolite kinetics: enalaprilat as a generated versus preformed metabolite.

Studies in the once-through perfused rat liver with the simultaneous delivery of 14 C-enalapril and its polar diacid metabolite, 3H-enalaprilat, revealed different extents of elimination (exclusively by biliary excretion) for the generated (14C-enalaprilat) and preformed (3H-enalaprilat) metabolite (18 and 5% dose) [Pang, Cherry, Terrell, and Ulm: Drug Metab. Dispos. 12, 309-313 (1984)]. The present re-examination of data provided an explanation for these discrepant observations: enalaprilat, being a polar dicarboxylic acid, encounters more of a diffusional barrier than its precursor, enalapril, an ethyl ester of enalaprilat. Programs written in Fortran 77 on mass balance relationships were employed to simulate data upon varying the diffusional clearances for drug (CLd) and metabolite [CLd(mi)] from 1 to 5000 ml/min. The metabolic and biliary intrinsic clearances for drug and metabolite were found by trial and error such that the combinations of all clearance parameters yielded data similar to enalaprilat, and 3H-enalaprilat. Our finding indicated that the diffusional clearance for enalaprilat was low (2 ml/min) compared to that of enalapril (75 ml/min). The presence of a diffusional barrier for enalaprilat retards entry of the preformed metabolite into hepatocytes but prevents efflux of the intracellularly formed generated metabolite into sinusoidal blood, thereby enhancing generated metabolite elimination.

Animals↗
PubMedDate not supplied

Effect of diffusional barriers on drug and metabolite kinetics.

Previous experimental and simulation studies have alluded to the presence of a diffusional barrier for enalaprilat, the polar, dicarboxylic acid metabolite of enalapril, entering hepatocytes. The present study examined the roles of diffusional clearances of drug and metabolite on the distribution and elimination characteristics in liver. The hepatic intrinsic clearances for enalapril (26.1 ml/min) and enalaprilat (0.7 ml/min), found in a previous study, were used for simulation because, along with their given diffusional clearances (75 and 2 ml/min, respectively), they yielded a high extraction ratio for drug (E = 0.86) and a poor extraction ratio for the preformed metabolite (E = 0.05). While maintaining the intrinsic clearances and hepatic blood flow rate (10 ml/min) constant, only drug and metabolite diffusional clearances were altered. The liver was modeled as three (blood, liver tissue, and bile) compartments, with blood flowing into sinusoids of uniform length L. Blood (sinusoidal) and tissue concentrations of drug and generated and preformed metabolites, at any point x along L and under linear kinetic conditions, were approximated numerically by computer simulations and expressed as the length-averaged or mean concentrations. The factors underlying drug and metabolite (preformed and generated) concentrations, hepatic clearances and elimination rates, and their interrelationships were illustrated graphically, emphasizing the roles of diffusional clearances for drug and metabolite on their spatial distributions and elimination in liver.

Animals↗
PubMedDate not supplied

Complications in the estimation of hepatic blood flow in vivo by pharmacokinetic parameters. The area under the curve after the concomitant intravenous and intraperitoneal (or intraportal) administration of acetaminophen in the rat.

Hepatic blood flow can be estimated from the area under the blood or plasma concentration-time curve of a drug following an intravenous dose and either an oral or intraperitoneal dose. The validity of the method depends on several factors which alter the area under the curve, that is, hemodynamic interactions due to the drug or its metabolites, the use of plasma concentration as opposed to blood concentration data, incomplete absorption on oral or intraperitoneal administration, enterohepatic recycling of the drug or its metabolite, and the presence of extrahepatic metabolism. The validity of the method was tested in rats with tracer doses of acetaminophen. After the simultaneous administration of an iv dose of 14C-acetaminophen and an intraportal dose of 3H-acetaminophen to rats, the availability after the first-pass hepatic extraction of acetaminophen in rats was 0.56 +/- 0.05. Hepatic blood flow estimated by the area under the curve for the respective routes of administration was 78.1 +/- 16.1 ml/min/kg. However, after the simultaneous administration of an iv tracer dose of 14C-acetaminophen and an ip dose of 3H-acetaminophen, the apparent availabilities calculated from the areas under the curve were highly variable and tended to be greater (0.73 +/- 0.11). Thus the estimates of the hepatic blood flow also tended to be higher (159 +/- 65 ml/min/kg).

Acetaminophen↗