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E R Garrett

Publications and source records attributed to E R Garrett.

At least 37 records · Page 2Linked to original sources
PubMed1983

Prediction of stability in pharmaceutical preparations XX: stability evaluation and bioanalysis of cocaine and benzoylecgonine by high-performance liquid chromatography.

Specific, sensitive, reverse-phase high-performance liquid chromatographic (HPLC) assays of cocaine (I) and its hydrolysis products, benzoylecgonine (II) and benzoic acid (III), have been devised with analytical sensitivities as low as 15 ng/ml of plasma for I using spectrophotometric detection at 232 nm. Cocaine can be separated from its hydrolysis products by extraction at pH 7.5 with haloalkanes. Benzoylecgonine and benzoic acid can be extracted at pH 3.0 with 1-butanol. The evaporated residues were reconstituted in acetonitrile-water for HPLC assay. The assay was used to determine the stabilities of I and II in aqueous solutions, to establish log k-pH profiles at various temperatures, and to evaluate Arrhenius' parameters. Hydrolyses were by specific acid-base catalysis. Cocaine showed hydrogen and hydroxyl ion attack on protonated I with 40 and 90% proceeding through the benzoylecgonine route, respectively, as well as hydroxyl ion attack on neutral cocaine, with only 6% proceeding through the benzoylecgonine route. Cocaine is relatively unstable in the neutral pH range with a half-life of 5 hr in buffer at pH 7.25 and 40 degrees. Similar half-lives were observed in fresh dog plasma at 300 and 30 micrograms/ml, although one study at 0.5 microgram/ml indicated a doubling of the rate.

Buffers↗
PubMed1983

High-performance liquid chromatographic assay of methadone, phencyclidine, and metabolites by postcolumn ion-pair extraction and on-line fluorescent detection of the counterion with applications.

Methadone, phencyclidine, and their metabolites were extracted from plasma and separated on a high-performance liquid chromatographic (HPLC) column using the fluorescent 9,10-dimethoxyanthracene-2-sulfonic acid as a counterion. The chromatographed mobile phase was subsequently extracted on-line with chloroform. The separated organic phase, containing the fluorescent ion-pairs of the investigated amines, was analyzed in the flow cell of a fluorometer (excitation 380 nm, emission 445 nm). The phase separator volume was as small as possible to avoid dead volume. The method was also applied to the bioassay of cocaine with a sensitivity of 1-6 ng/ml of plasma. Application of these assays gave a red blood cell-plasma water partition coefficient for methadone of 3.39 +/- 0.26 (SD) in a concentration range up to 20 micrograms/ml, and demonstrated a time-dependent partition with a diffusion half-life of 1.44 min +/- 0.26 min (SD). The protein binding of methadone determined by ultracentrifugation was concentration dependent and varied between 75-62% at the highest concentration studied (9 micrograms/ml). The presence of the major metabolite did not have any influence on the protein binding. The results were confirmed by using the red blood cell-partitioning method to determine the protein binding.

Animals↗
PubMed1983

Pharmacokinetics of intravenous and oral 1,2-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucofuranose hydrochloride in the dog as a function of dose and characterization of metabolites.

The pharmacokinetics of 1,2-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucofuranose hydrochloride (1) was studied in dogs at intravenous and oral doses of 1-50 mg/kg. There was no significant difference between the electron-capture GLC of the heptafluorobutyric derivative of I and the radiochemical assay of chloroform extracts of plasma and urine for 1- to 20-mg/kg doses. Urinary amounts of I measured by GLC were 20% lower than radioassays of chloroform extracts at the 50-mg/kg dose. The pharmacokinetics of intravenous I was described by a two-compartment body model with sequential plasma half-lives of 7.5 +/- 0.7 and 136 +/- 6 min. No apparent dose-dependent pharmacokinetics for I was observed on intravenous or oral administration. The apparent volume of distribution of the central compartment, 13.1 +/- 0.7 liters, is approximately the volume of the total body water in a 20-kg dog. The apparent overall volume of distribution of 40.0 +/- 1.5 liters exceeds the total body water, indicative of sequestration of I in tissues. Total and renal clearances were 205 +/- 5 and 155 +/- 5 ml/min, respectively. The high renal clearance of I indicated an excess of tubular secretion. Renal clearance of I was not dependent on urine flow nor urine pH. Recovery of radioactivity in the feces after I was intravenously administered was less than 1%. Plasma protein binding of I was less than 5%, and the erythrocyte-plasma water partition coefficient was approximately unity. Compounds excreted in urine were separated into chloroform-extractable (pH 12), ethyl acetate-extractable (pH 2), and unextractable fractions which were further characterized by TLC. A multiple-extraction system was developed to estimate relative amounts and intrinsic partition coefficients of these extractable compounds from radioactivity counts of scraped plates and was applied tof the assay of these compounds in the urine after intravenous administration of I. There was a readily chloroform-extractable metabolite with an apparent partition coefficient of 3.3 and Rf 0.43 on TLC in the systems used. This apparent major metabolite could account for 8% of the administered radioactivity. Minor chloroform-extractable metabolites (0.8-3.3%) had lower apparent partition coefficients (0.26) but Rf values of 0.28 and 0.44 . Ethyl acetate-extractable compounds (1.3-2.7%) had an apparent partition coefficient of 0.81 with Rf values of 0.52 and 0.68. Three unextractable compounds had Rf values of 0.20, 0.50, and 0.62 and accounted for 0.16, 2.8, and 0.9% of the administered radioactivity.

Administration, Oral↗
PubMed1983

Plasmolysis, red blood cell partitioning, and plasma protein binding of etofibrate, clofibrate, and their degradation products.

Etofibrate (I), the ethylene glycol diester of clofibric and nicotinic acids, degrades almost equally through both half-esters with half-lives of approximately 10 and 1 min in fresh dog and human plasma, respectively. The nicotinate V degrades with half-lives of approximately 12 hr and 50 min in fresh dog and human plasma, respectively. Ester III and clofibrate VI degrade by saturable Michaelis-Menten kinetics in fresh human plasma, with similar maximum initial rates and respective terminal first-order half-lives of 12 and 26 min. Tetraethyl pyrophosphate at 100 micrograms/ml inhibited human plasma and red blood cell esterases permitting plasma protein binding and red blood cell partitioning studies. The red blood cell-plasma water partition coefficient was 5.4 for 0.2-80 micrograms/ml of I. Clofibrate (VI) showed a saturable erythrocyte partitioning that decreased from 7.8 (10 micrograms/ml) to 1 (50 micrograms/ml). The strong binding of I and VI to ultrafiltration membranes necessitated the determination of their plasma protein binding by the method of variable plasma concentrations of erythrocyte suspensions to give 96.6% (0.2-80 micrograms/ml) and 98.2% (13.6-108.4 micrograms/ml) binding, respectively. Methods for the determination of the parameters of saturable and nonsaturable plasma protein binding for unstable and membrane-binding drugs by the method of variable plasma concentrations in partitioning erythrocyte suspensions are presented.

Animals↗
PubMed1982

Predictions of stability in pharmaceutical preparations XIX: Stability evaluation and bioanalysis of clofibric acid esters by high-pressure liquid chromatography.

Specific, sensitive, reversed-phase high-pressure liquid chromatographic assays of clofibric acid esters, clofibrate and etofibrate, and their hydrolysis products, clofibric acid and its monoglycolate and nicotinic acid and its monoglycolate, have been developed in aqueous solution and in biological fluids. Sensitivities of 100 ng/ml of injected mobile phase, a 10-fold increase over existing methods, are reported. Plasma concentrations as low as 200 ng/ml can be analyzed easily in the miscible phase after acetonitrile denaturation. The compounds and their products can be extracted with haloalkane solvents. The extracts were evaporated, reconstituted, and assayed in minimal amounts of mobile phase, resulting in sensitivities of 10 ng/ml of plasma. Conditions are presented that minimize interferences with plasma components. The assay was used to determine the stability of the clofibric acid esters in aqueous solutions, to establish log k-pH profiles at various temperatures, and to evaluate Arrhenius parameters. Hydrolysis was by specific acid-base catalysis. The initial product of etofibrate solvolysis at pH greater than 6 is the monoglycol ester of clofibric acid; at pH less than 3, it is the monoglycol ester of nicotinic acid. Clofibric acid esters are highly unstable to mild alkali (1-3 hr at pH 10 and 30 degrees); even in the estimated pH range of maximum stability, they have half-lives of 100-200 days at 30 degrees. They have half-lives of 4-7 min at 37.5 degrees in fresh dog plasma, and data presented indicate that clofibric acid monoglycolate is an initial product of etofibrate solvolysis.

Animals↗
PubMed1982

Properties, stability, assay, and preliminary pharmacokinetics of the immunomodulatory 1,2-O-isopropylidene-3-O-3'(N',N'-dimethylamino-n-propyl)-D-glucofuranose hydrochloride.

1,2-O-Isopropylidene-3-O-3'(N',N'-dimethylamino-n-propyl)-D -glucofuranose hydrochloride (I) is a new agent with claimed immunomodulatory action and antiviral activity. Thin-layer chromatographic procedures and identifying tests were developed to separate the drug, its synthetic precursors, and solvolytic products, and were applied to stability studies. It is stable in 0.1 N NaOH at 60 degrees where its acid solvolysis product, 3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucose is readily degraded. The partition coefficient of I (pK'a = 9.28) between chloroform and plasma was 6.4 +/- 0.2 SEM between pH 10.5 and 11.0. Plasma and urine (0.5 ml) adjusted to pH 11.0 were extracted with 10 ml of chloroform and the extract evaporated. The reconstituted residue in 50 microliters of benzene, with the disopropylaminoethyl analog of I as an internal standard, was derivatized with 50 microliters of heptafluorobutyric anhydride at 60 degrees for 45 min and was evaporated and reconstituted in 100 microliters of benzene to be assayed for I by GLC with electron capture detection with a sensitivity of 5 ng/0.5 ml of biological fluid. The procedure was applied to pharmacokinetics in the dog and a two-compartment body model was observed with a terminal half-life of 103-130 min. At the 40-mg dose, 60-64% was excreted renally unchanged and 20-34% as unidentified metabolites. At the 200-mg dose 82-85% was excreted unchanged and 15-17% as unidentified metabolites. The respective renal clearances of I were 135 and 163 ml/min. The respective total clearances of I were 204 and 191 ml/min. These metabolites were apparently unextracted with chloroform from biological fluids at pH 11 and the liquid scintillation counting (LSC) assay of extracted radiolabeled I appeared synonomous with the GLC assay of I in such fluids.

Adjuvants, Immunologic↗
PubMed1982

Pharmacokinetics of the immunomodulatory 1,2-O-isopropylidene-3-O-3'-(N',N'-dimethyl-amino-n-propyl)-D-glucofuranose hydrochloride in normal human volunteers.

1,2-O-Isopropylidene-3-O-3'(N',N'-dimethyl-amino-n-propyl)-D-glucofuranose hydrochloride, I, is a substituted sugar with claimed immunomodulatory action. Pharmacokinetic studies in 10 volunteers (bolus i.v., 100 mg) showed respective half-lives for each exponential in the sum of two exponentials that characterized plasma level decay with time of 4.6 +/- 0.4 (SEM) min, t1/2(lambda 1), and 244 +/- 20 min, t1/2(lambda 2)), The total and renal clearances were 277 +/- 20 and 254 +/- 18 (SEM) ml/min, indicative of tubular secretion. Urinary recovery was 93 +/- 2%. The estimated volumes of distribution of the central compartment and overall equilibrated tissues were 14.7 +/- 1.9 and 96 +/- 8 liters, respectively. Sequential daily oral administration of large amounts in capsules (1.2, 2.1, 2.9, 4.1, and 5.0 g) permitted an estimate of 63 +/- 4 (SEM)% bioavailability from urinary recovery of drug, with estimated terminal half-lives of 454 +/- 25 min from minimal data. Orally administered 2.03 g showed a rapid absorption (t1/2 = 10 min) after a lag time of 23 min, and a terminal plasma half-life of 344 min. Plasma protein binding of I was negligible. The erythrocyte/plasma water partition coefficient was close to unity.

Adjuvants, Immunologic↗
PubMed1981

Prediction of stability in pharmaceutical preparations XVIII: application of high-pressure liquid chromatographic assays to study of nafronyl stability and bioanalysis.

Specific, sensitive, reversed-phase high-pressure liquid chromatographic assays of nafronyl (I) and its acidic metabolite and hydrolysis product (II) were developed in aqueous solutions and in biological fluids with sensitivities of 100 ng/ml using butacaine as the internal standard and spectrophotometric detection of 224 nm. Heparinized plasma can be analyzed easily in the organic phase immediately after acetonitrile denaturation. Both I and II can be extracted with haloalkane solvents, and the extracts are evaporated, reconstituted, and assayed in a minimal amount of acetonitrile. Conditions are presented that minimize the interference of II and extracted plasma components. The assay was used to determine the stability of nafronyl in aqueous solutions, to establish its log k-pH profiles at various temperatures, and to evaluate the Arrhenius parameters. Nafronyl is hydrolyzed by specific hydrogen-ion (15.2 kcal/mole) and hydroxide-ion (7.72 kcal/mole) catalysis of the neutral species and specific hydroxide-ion catalysis (5.91 kcal/mole) of the protonated species. The pH of maximum stability is 3.0, and pH 5.4 is the maximum that can be tolerated at 30 degrees, with a 10% solvolysis in 3 years. The half-life of nafronyl at 30 degrees was 7 days at pH 7, 12 hr at pH 10, and 21 min in 0.5 N NaOH. Since nafronyl has a half-life of 3.2 hr in heparinized dog plasma at 25 degrees, blood samples for pharmacokinetic studies of nafronyl must be assayed immediately after sampling. The partition coefficients of I and II determined as functions of pH permit the extraction of both compounds at pH 4.5, but only I can be extracted at pH values above 9.5.

Animals↗
PubMed1980

Pharmacokinetics of morphine and its surrogates IV: Pharmacokinetics of heroin and its derived metabolites in dogs.

The pharmacokinetics of intravenously administered heroin and its derived metabolites, 6-O-monoacetylmorphine, morphine, and the glucuronidated conjugates of morphine, were studied in dogs at doses of 0.1-0.5 mg/kg. The spontaneous hydrolysis of the sampled biological fluids was inhibited by tetraethyl pyrophosphate so that the heroin concentration at the times of sampling could be analyzed for the first time. Heroin is concomitantly rapidly metabolized and distributed among body tissues. Metabolic clearance of 2916 +/- 321 ml/min are largely extrahepatic and are sixfold greater than hepatic blood flow. Nevertheless, the terminal half-life of 60-90 min resembles that of morphine and is maintained by the rate-determining return of distributed heroin from esterase-free tissues. Normal renal clearances of 43 +/- 6 ml/min result in 1.6 +/- 0.2% of the dose being renally excreted unchanged. The large overall volume of distribution, 344 +/- 60 liters, is indicative of heroin's wide distribution and lipophilicity, which rapidly equilibrates heroin in the plasma with the cerebrospinal fluid. Heroin is concomitantly metabolized almost equally to 6-O-monoacetylmorphine and morphine. The monoacetylmorphine is metabolized concomitantly to morphine and glucuronide conjugates in a 4:3 ratio and exercises its own activity. Its time course is close to that of heroin, although the total clearance (2200 ml/min) and overall volumes of distribution (90-170 liters) were less. The integrated model of transformations and eliminations was constructed with concomitant metabolism of the heroin metabolite, 6-O-monoacetylmorphine, to morphine and glucuronide conjugates. The assumption that the glucuronide conjugates partition into the bile and systemic circulation in the same ratio as does the conjugate of the derived morphine metabolite gave pharmacokinetic parameters consistent with the morphine pharmacokinetics studied previously and provided excellent fits of the plasma level-time curves of all of the derived metabolites of heroin.

Animals↗
PubMed1979

Pharmacokinetics of morphine and its surrogates II: methods of separation of stabilized heroin and its metabolites from hydrolyzing biological fluids and applications to protein binding and red blood cell partition studies.

The inhibition of the spontaneous hydrolysis of heroin in fresh dog plasma on blood (t1/2 = 8 min) is effected by 10 mg of sodium fluoride/ml (t1/2 = 40 min) and 35 microgram of tetraethyl pyrophosphate/ml (t1/2 = 415 min). Tetraethyl pyrophosphate is the inhibitor of choice and gives the same stability for heroin as in phosphate buffer. Aged plasma loses its enzymatic efficiency. Heroin in cerebrospinal fluid hydrolyzes at rates similar to those in buffer. Modified extraction procedures developed for enzyme-inhibited plasma at pH 4.5 have high extraction efficiencies (86--100%) and permit isolation of undergraded heroin from its metabolites. Separations of heroin and metabolites from enzyme-inhibited plasma were effected by described high-pressure liquid chromatographic systems and from TLC with elution of pertinent developed spots. Efficiencies of these TLC recoveries were 81 +/- 1% for heroin and 82 +/- 1% for morphine. Contrary to the literature, heroin has significant protein binding where 40% of that not bound to an ultrafiltration membrane is bound to dog plasma proteins. The apparent partition coefficient is 1.4 +/- 0.2 between red blood cells and plasma water, and it is 0.8 +/- 0.1 between red blood cells and dog plasma.

Animals↗
PubMed1979

Pharmacokinetics of morphine and its surrogates. III: Morphine and morphine 3-monoglucuronide pharmacokinetics in the dog as a function of dose.

The pharmacokinetics of morphine and its derived metabolite, morphine 3-monoglucuronide, were studied in normal and bile-cannulated dogs. High doses (7.2-7.7 mg/kg iv) caused renal and biliary shutdowns and time lags in urinary drug and metabolite excretion and in biliary secretion of the hepatically formed conjugate. Intermediate doses (0.41-0.47 mg/kg iv) inhibited urine flow but not renal clearance. Low doses (0.019-0.07 mg/kg iv) had no apparent effect. Dose-related effects on the total, metabolic, and biliary clearances imply saturable enzymes and/or dose-inhibited hepatic flows, accounting for the major elimination half-lives of 83 +/- 8 and 37 +/- 13 min at the high and low doses, respectively. The slow terminal phase in plasma morphine and metabolite elimination and urinary accumulation is due apparently to the enterohepatic metabolite recirculation after biliary excretion, gastrointestinal hydrolysis, and hepatic first-pass reconjugation. Bile-cannulated dogs showed no fecal drug and no slow terminal plasma and urine elimination phases. Intravenous morphine 3-monoglucuronide was eliminated only renally and showed neither biliary excretion nor prolonged hepatically formed glucuronide elimination. Hepatic morphine clearances at normal therapeutic doses parallel hepatic blood flow and explain the lack of oral morphine bioavailability by anticipating complete first-pass liver metabolism. Renal morphine and morphine conjugate clearances were 85 (+/- 9 SEM) and 41 (+/- 4 SEM) ml/min, respectively, indicating glomerular filtration for the latter and glomerular filtration plus tubular secretion for the former. Urinary morphine and morphine conjugate excretion accounted for approximately to 83% of the dose. Biliary secretion accounted for 11-14% of the dose. Morphine showed dose-independent plasma protein binding of 36 (+/- 1 SEM) % and a red cell-plasma water partition coefficient of 1.11 +/- 0.04 SD. New equations were developed to model the discontinuous morphine and morphine metabolite pharmacokinetics.

Animals↗
PubMed1978

Stability of tetrahydrocannabinols II.

The biphasic degradation of delta9-tetrahydrocannabinol (I), as monitored by flame-ionization GLC, produced delta8-tetrahydrocannabinol (II), cannabidiol (X), 9-hydroxyhexahydrocannabinol (VI), 9,10-dihydro-9-hydroxyisocannabidiol (VI), and and 6,12-dihydro-6-hydroxycannabidiol (VIII) in acidic solutions. Further identification was made by GLC, mass spectrometry, and comparison with authentic samples. Only II and IV were produced above pH 4 in the neutral region by first-order kinetics. The acidic degradation of cannabidiol (X) gave I and the products of the acidic degradation of I. The initial phase of acidic I degradation was assigned to the development of solvolytic equilibria among I, VIII, X, and, possibly, isocannabidiol (IX), with the concomitant production of II and IV. Compounds VIII, IX, and X did not appear in the neutral region since ether cleavage occurred only in strong mineral acids. Hydration of the delta9-double bond resulted only in acid-catalyzed equilibria of cleaved ethers with the delta8-configurations and characterized the second phase of acid degradation of I. Cannabinol and hexahydrocannabinol were found together in several cases due to the disproportionation of I as catalyzed by silicic acid, silica gel, and chloroform.

Chemical Phenomena↗
PubMed1978

Kinetics of plasma coagulation and lysis I: Basic kinetic model for time course of coagulation-lysis systems and its potential application to clinical studies.

The time courses of coagulation and coagulation-lysis were spectrophotometrically monitored after the addition of thrombin or thrombin-streptokinase to plasma, diluted 1:5 with normal saline, obtained from normal and presumably abnormal subjects. The kinetics of clotting, after an initial lag period of 0.5-1.5 min, demonstrated essentially first-order dependence on the amount of fibrinogen available to form the clot, and the asymptotic absorbance was independent of thrombin concentration. The rate of clotting was a function of added thrombin, and the ratios of the rate constants at 2.5 and 1.25 units of thrombin/ml of undiluted plasma were 1.65 +/- 0.03 SEM. At early times, the coagulation-lysis curve with thrombin-streptokinase could be superimposed on the clotting curve with thrombin alone for a given plasma with minor compensation for variable lag times. Subsequently, the curves diverged; lysis was monitored by the decrease in absorbance of the coagulation-lysis system. The rate of fibrinolysis increased with streptokinase concentration and was a function of the extent of lysis, and it permitted the description of the kinetics of lysis by a pseudoautocatalytic mechanism where the bimolecular rate constant appears proportional to streptokinase concentration. Ranges of clotting and lytic parameters for the plasma of normal subjects are given, and their potential use in diagnosing abnormalities is described.

Blood Coagulation↗
PubMed1978

Pharmacokinetics of morphine and its surrogates I: comparisons of sensitive assays of morphine in biological fluids and application to morphine pharmacokinetics in the dog.

A sensitive isotope derivatization assay was developed to quantify morphine in biological fluids in the nanogram per milliliter range. Morphine, derivatized with 3H-dansyl chloride, was separated from the reaction products by TLC. The spots were scraped from the plate, and the eluted radioactivity was determined by liquid scintillation. The standard deviations of this morphine assay were +/- 18.6 ng/ml in 100 microliter of plasma and +/- 1.86 ng/ml in 1 ml of plasma. The GLC analysis of pentafluoropropionated morphine in the range of 0--5 ng of morphine/ml of plasma had a standard deviation of +/- 0.46 ng/ml when 1 ml of plasma was taken. Liquid scintillation spectrometric analysis of 14C-morphine had a sensitivity of 1.5 ng/ml of plasma at double the background. There were no significant differences among the liquid scintillation, electron-capture GLC, and radioisotpoe derivatization methods for morphine obtained from the plasma of a dog given 14.00 mg iv of morphine. Morphine conjugates were assayed as morphine after the acid hydrolysis of plasma and urine preextracted to remove unconjugated morphine, and the equivalence of various methods was demonstrated to monitor plasma and urine pharmacokinetics in a dog.

Animals↗
PubMed1978

Pharmacokinetics of papaverine hydrochloride and the biopharmaceutics of its oral dosage forms.

The pharmacokinetics of completely metabolized papaverine hydrochloride were characterized by a linear sum of three exponentials on intravenous administration with respective 1.5, 19 and 107 min apparent half lives. There was a time-dependent partition from plasma water into red blood cells with an apparent half life of 1.5--3 min. The partition coefficient normally ranged between 8 and 15 at therapeutic levels but approached unity at high plasma concentrations to indicate a saturable partition. Apparent compartmental volumes of distribution referenced to total concentrations in the plasma were 4.3--4.8, 11--13 and 20--25 liters. Protein binding was 91--95%. The hepatic clearance of blood was 960 ml/min, corresponding to a hepatic efficiency of 69%, and indicated that the clearance of protein-bound drug was consistent with the observed first pass metabolism of 70% for oral solutions. No dose dependency was observed on intravenous administration or on oral administration of solutions and tablets. Tablets with release lag times of 10--15 min showed relative bioavailabilities of 52%. Two different lots of sustained release capsules showed 68 and 89% relative bioavailabilities. Release lag times among capsules ranged between 0 and 170 min. Loo-Riegelman calculations and analog computer fittings were consistent with a half life of absorption from oral solutions of 19 min and zero order release rates from tablets and sustained release capsules. Chronic studies of tablets q.i.d. and capsules b.i.d. confirmed lack of accumulation. An appropriately designed 300 mg sustained release capsule, b.i.d., for an arbitrary plasma level of 0.200 microgram/ml should have one tenth the release rate of the studied capsules.

Administration, Oral↗