Biomedical subjects

D D Tang-Liu

Publications and source records attributed to D D Tang-Liu.

At least 37 records · Page 2Linked to original sources

PubMed1990

A corneal perfusion device for estimating ocular bioavailability in vitro.

An in vitro method for investigating drug penetration across the cornea from acute doses has been developed. The donor (epithelial or tear) side of a corneal chamber similar to those used by Edelhauser and co-workers was modified with a reduced-volume insert so that the donor side volume approximated 6% of the receiver (endothelial or aqueous humor) chamber volume. Fluid was pumped through the anterior chamber to simulate the physiologic tear turnover in vivo. The receiver chamber was bubbled with oxygen:carbon dioxide (95%:5%) to aerate and circulate the fluid. We investigated the in vitro ocular bioavailability of several marketed ophthalmic drug formulations using this model (0.03% flurbiprofen, 0.5% levobunolol, 0.1 and 0.25% fluorometholone, and 1% prednisolone acetate). At 1 min after the dose administration, drug was eluted from the donor chamber at a dose turnover rate of 12%/min. In all experiments, a small percentage of the applied dose penetrated the cornea. Using this chamber device, the ocular bioavailability via corneal absorption ranged between 5 and 16% for solution formulations, whereas the ocular bioavailability for the suspension formulations was less than 0.3%. The major portion of the administered dose was recovered from the donor side effluent. This observation was consistent with findings showing low ocular bioavailability of ophthalmic preparations due to the rapid precorneal washout in vivo. The extent of drug penetrating as its corneal metabolite in the model correlated well to in vitro corneal metabolism rate constants. The new model opens several potentially useful areas of research into ocular absorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗

PubMed1990

Corneal and conjunctival/scleral penetration of p-aminoclonidine, AGN 190342, and clonidine in rabbit eyes.

The ocular penetration pathways of three alpha 2-adrenergic agents (p-aminoclonidine, AGN 190342, and clonidine) were investigated in rabbits both in vitro and in vivo. The corneal permeabilities of the compounds correlated positively with their octanol/water distribution coefficients. The ocular drug absorption via corneal and conjunctival/scleral penetration routes was evaluated separately after drug perfusion in vivo. In most cases, the corneal route was the major pathway for the intraocular drug absorption. However, the conjunctival/scleral penetration pathway was the predominant pathway for the delivery of p-aminoclonidine, the least lipophilic compound among the three drugs, to the ciliary body. The drug concentration in the iris was contributed mainly by the corneal route and correlated well with drug lipophilicity.

Absorption↗

PubMed1989

Ocular biodistribution of clonidine after topical application with ophthalmic rods or solution.

We compared the ocular tissue and systemic blood distribution patterns of clonidine, an alpha 2-adrenergic agonist with ocular hypotensive activity, after topical application with ophthalmic rods or ophthalmic solution (eyedrops) in rabbits. We measured tissue concentrations at 0-240 minutes after administration with rods containing 5 micrograms, 10 micrograms, or 20 micrograms clonidine, or a 0.125% (62.5 micrograms) solution. The delivery efficiency of the rods was 65 - 71%. The rods and eyedrops had similar absorption and distribution patterns intraocularly and in systemic blood. Tissue concentrations of clonidine achieved were proportional to the dose delivered; peak ocular tissue concentrations were reached within 20 minutes (except for the lens). Clonidine concentrations were: tears greater than cornea greater than iris/ciliary body greater than or equal to aqueous humor greater than lens. We concluded that the ophthalmic rod offers a viable alternative to ophthalmic solution for the topical delivery of clonidine.

Administration, Topical↗

PubMed1988

Percutaneous and systemic disposition of hexamethylene lauramide and its penetration enhancement effect on hydrocortisone in a rat sandwich skin-flap model.

The percutaneous absorption and distribution profile of hexamethylene lauramide (hexahydro-1-lauroyl-1H-azepine) were examined using a rat skin-flap model. After a topical dose to the skin flap, the drug concentrations in the vasculature at the site of drug application and in the systemic blood were monitored simultaneously. Hexamethylene lauramide penetrated the skin and reached a steady state in stratum corneum, viable epidermis, dermis, and cutaneous blood in 3 hr. Its concentration in the skin was much higher than that in the blood. Its apparent concentration in the epidermis was 19 times that in the dermis and about 3000 times that in the cutaneous blood. The percutaneous absorption of 14C-hexamethylene lauramide resulted in ascending systemic blood concentrations throughout the experimental period, whereas the cutaneous blood levels remained steady. The topically absorbed hexamethylene lauramide was quantitatively recovered in urine (85%) and feces (13%). The half-lives of urinary and fecal excretion of 14C-hexamethylene lauramide were 17 and 30 hr, respectively. Hexamethylene lauramide, when topically coadministered in an experimental formulation, enhanced the skin penetration of hydrocortisone with increased drug contents in the stratum corneum (2-fold) and with increased hydrocortisone concentrations in the cutaneous blood (3.4-fold) and the systemic blood (3.5-fold). The results indicated that the high concentration and retention of hexamethylene lauramide in stratum corneum and viable epidermis may contribute to its penetration enhancement effect in the skin. A steady state in percutaneous tissues was observed before the drug reached distribution equilibrium systemically. The systemic blood concentration of a topically applied agent therefore may not reflect its percutaneous kinetic processes before a systemic distribution equilibrium is reached.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗

PubMed1988

The effect of azone on ocular levobunolol absorption: calculating the area under the curve and its standard error using tissue sampling compartments.

Methods of calculating the area under the concentration-time curve and the associated standard error are proposed for studies in which each animal contributes one independent data point to a pool of data. This approach can be used for data analysis in bioequivalence studies employing tissue sampling compartments. Application of this method indicated that an azone-containing ophthalmic formulation of levobunolol did not produce better ocular bioavailability than a formulation containing no penetration enhancer.

Animals↗

PubMed1988

Ocular metabolism of levobunolol.

Dihydrobunolol is an ocular metabolite equipotent to levobunolol. In order to understand the formation and distribution of dihydrobunolol after an ophthalmic dose of levobunolol, studies in vitro and in vivo were initiated. The metabolism of levobunolol to dihydrobunolol was investigated using an organ-culture technique. The corneal formation of dihydrobunolol was pH-dependent and increased as the pH of the incubation fluid increased from 5.3 to 8.3. Its formation from levobunolol was saturable with Vmax and Km values (pH 7.4) of 13.2 nmol/min/gm of cornea and 1.48 mM, respectively. After a topical dose of 0.5% levobunolol hydrochloride to rabbit eyes, rapid absorption of levobunolol and facila formation of dihydrobunolol were noted. The drug concentration in the eye drop (approximately 17 mM) was much higher than Km and would saturate the epithelial reductase system in the cornea during drug absorption. The total concentrations of levobunolol and dihydrobunolol in ocular tissues were in the micromolar range throughout the experimental period. Dihydrobunolol, after distribution equilibrium, was the major drug-derived species in the cornea, aqueous humor, and iris-ciliary body. The study results indicated pH-dependent and capacity-limited formation of dihydrobunolol in the cornea. Buffering capacity and the drug concentration in the ophthalmic dose are important formulation strategies because they may affect the rate and the extent of dihydrobunolol formation in the epithelial cell layers of the cornea.

Animals↗

PubMed1987

Disposition of levobunolol after an ophthalmic dose to rabbits.

The ocular and systemic disposition of levobunolol (LBUN), an antiglaucoma agent, was studied in albino rabbits. After topical administration to eyes, LBUN was rapidly adsorbed, with 2.5% of the dose bioavailable to the intraocular tissues as intact drug and 46% to the systemic circulation. On passage across the cornea, approximately 4.7% of a topically applied LBUN dose was biotransformed to dihydrolevobunolol (DHB), and subsequently became bioavailable to intraocular tissues. The major sites of ocular metabolism were the cornea epithelium and the iris-ciliary body. Another 12% of the topical LBUN dose entered the systemic circulation as DHB after presystemic biotransformation. Our study indicated a rapid absorption of LBUN into the aqueous humor after topical dosing. The tpeak was 15 min after dosing and the Cmax was 4 micrograms/mL. Dihydrolevobunolol (DHB) was formed steadily and reached a maximum in the aqueous humor 45 min after dosing. After distribution equilibrium had been reached, the aqueous humor concentrations of both LBUN and DHB declined. Six hours after dosing, the concentration of DHB in the aqueous humor was approximately 10 times higher than that of its parent compound. Because DHB is equivalent to its parent compound in beta-blocking activity, its formation in the rabbit eye may contribute to the pharmacodynamic effects observed after topical doses of LBUN.

Animals↗

PubMed1987

Relationship between the ocular and systemic disposition of flurbiprofen: the effect of altered protein dynamics at steady state.

The differences in flurbiprofen disposition in the aqueous humor and the plasma were examined after systemic doses. Steady state plasma concentrations of flurbiprofen (20-60 micrograms/mL) were achieved via intravenous infusion to albino rabbits. Flurbiprofen demonstrated linear systemic kinetics throughout the dosing range, with constant body clearance and unbound fraction in plasma. At steady state, aqueous humor drug concentrations depended on the corresponding plasma drug concentration. Two clearance terms--CLS----O, the systemic clearance to ocular tissues, and CLO----S, the ocular clearance to systemic circulation--were used. After systemic doses, the drug concentration in the aqueous humor was related to that in the plasma as well as to the ratio of these two clearances. Flurbiprofen was extensively bound to plasma proteins and showed limited ocular distribution; its CLS----O to CLO----S ratio was very small. Thus, the concentration of flurbiprofen in the aqueous humor after systemic doses was lower than that obtained after ophthalmic doses. A plasmapheresis technique was utilized to lower the plasma protein concentrations to 60% of normal levels. As a consequence, flurbiprofen demonstrated reduced aqueous humor protein concentrations, increased unbound fractions in the plasma and the aqueous humor, elevated aqueous humor drug concentrations, and elevated total body clearance. The unbound body clearance stayed unchanged. Our study indicated that a drug should present a significant CLS----O/CLO----S ratio in order to achieve therapeutic concentrations in the eye via systemic doses. The drug-protein binding kinetics can be different between the plasma and the aqueous humor circulations. Because the ocular compartment is very small compared to the overall systemic distribution of flurbiprofen, it has little effect on the steady state systemic concentrations.

Animals↗

PubMed1987

Plasma levobunolol levels following topical administration with reference to systemic side effects.

We determined the plasma level of levobunolol in normal volunteers after a single topical instillation of 0.5 or 1% levobunolol in both eyes, and after twice-daily instillations for 1 week. Levobunolol levels were detected within 1 h following acute instillation. During the study, mean plasma levels ranged from 0.1 to 0.3 ng/ml for the 0.5% group and 0.3 to 0.6 ng/ml for the 1% group. The highest individual plasma level was 1.2 ng/ml, which occurred in 1 patient receiving 1% levobunolol. After 1 week of twice-daily instillation mean plasma levels were similar to those observed after acute instillation. Minimal cardiovascular changes were observed in the 0.5% group while decreases in heart rate and systolic blood pressure were observed in the 1% treatment group.

Administration, Topical↗

PubMed1985

Comparison of the urinary metabolite profile of caffeine in young and elderly males.

The urinary metabolite profile of caffeine was compared in a group of seven healthy young men aged 18-29 years and in a group of five healthy elderly men aged 66-71 years. All subjects were given 5 mg/kg doses of caffeine as an aqueous oral solution or an intravenous infusion on two separate occasions in a randomized crossover design. Urine samples were collected for 24 h after dosing and analysed for caffeine and eleven of its metabolites by high-performance liquid chromatography. The effects of age, route of administration, and order of administration by route on the metabolite profile of caffeine were examined. The route of administration and the order of administration by the two routes were found not to influence the urinary metabolite pattern significantly. The urinary metabolite profile did not vary substantially with age except for the observation that significantly greater amounts of 1-methyluric acid, 7-methyluric acid and 1,7-dimethyluric acid were excreted by the elderly subjects.

Adult↗

PubMed1984

Ocular and systemic bioavailability of ophthalmic flurbiprofen.

Flurbiprofen, a nonsteroidal antiinflammatory agent which is not ocularly metabolized, was employed as a probe compound to investigate the drug kinetic relationship between systemic and ocular humoral circulation. The ocular and systemic bioavailabilities of topically applied flurbiprofen were also quantitated. Anesthetized albino female rabbits received flurbiprofen doses intracamerally, topically, and intravenously at 2 to 4 week intervals. Aqueous humor and plasma were used as the sampling compartments. Plasma clearance values of flurbiprofen were 6.77 and 7.87 ml/min, after 6-mg and 208-micrograms intravenous doses, respectively. These values were not significantly different and indicated no dose-dependent disposition kinetics over a 30-fold dose range. Both ocular and systemic flurbiprofen dispositions followed a biexponential pattern with a rapid distribution phase. The systemic and ocular distribution half-lives of flurbiprofen were 12 min and 15 min, respectively. The plasma elimination half-life was 74 min and the aqueous humor elimination half-life was 93 min. The latter approximated the turnover rate of aqueous humor and suggested that aqueous humor drainage was the major process of flurbiprofen elimination from the globe. About 99% of flurbiprofen is bound to plasma protein. At distribution equilibrium, the plasma and aqueous humor concentrations of flurbiprofen differed by a hundredfold, suggesting that only free drug entered the aqueous humor after the administration of a systemic dose. In the ophthalmic studies, right eyes were instilled with 50 microliters of 0.3% flurbiprofen in saline (dose = 150 micrograms), and left eyes were instilled with 50 microliters of 0.15% flurbiprofen in saline (dose = 75 micrograms). When the area of the aqueous humor concentration-versus-time curve values was normalized by the administration dose, the 75-micrograms dose was 30% more available to ocular tissues than was the 150-micrograms dose. This demonstrated a disproportionate relationship between the administered dose and the fraction absorbed. The intracameral dose was considered to be completely bioavailable for intraocular effects. The ocular bioavailability of the ophthalmic dose was defined by using intracameral administration as a standard measurement. The ocular bioavailabilities of the 75-micrograms and 150-micrograms topical flurbiprofen doses were 10% and 7%, respectively. Systemic bioavailability after topical administration of 225 micrograms of flurbiprofen was 74%.

Administration, Topical↗

PubMed1983

Dependence of renal clearance on urine flow: a mathematical model and its application.

A mathematical model is developed to explain the dependence of renal clearance on urine flow rate. The model is tested using human data from the literature on compounds that are neither secreted nor reabsorbed by active or pH-sensitive mechanisms. The physiologically derived model explains and predicts the relationship between renal clearance and urine flow for a broad spectrum of compounds (i.e., butabarbital, chloramphenicol, creatinine, ethanol, theophylline, and urea) for which appropriate data are available.

Absorption↗

PubMed1983

Disposition of caffeine and its metabolites in man.

The disposition of caffeine and its metabolites was studied in six healthy subjects by use of sensitive and specific assays. The primary degradation of caffeine in man was found to be N-demethylation and/or ring oxidation to theophylline, paraxanthine, theobromine and 1,3,7-trimethyluric acid. These compounds were further degraded to dimethylated uric acids, monomethylxanthines and monomethyluric acids. About 3 and 6% of the drug was converted to theophylline and theobromine, respectively. The elimination of paraxanthine after its formation did not follow linear kinetics. A large urine recovery of 1-methylxanthine after caffeine administration in comparison with the amount recovered after administration of theophylline suggests an inhibitory effect on the degradation of this metabolite by either caffeine itself or another metabolite of caffeine. Caffeine and its primary metabolites, dimethylxanthines, were extensively reabsorbed in the renal tubule. Their renal clearances were highly urine flow-dependent and their urinary excretion varied with urine output during the study. About 70% of the dose was recovered in the urine. Postulated degradation pathways of caffeine are discussed.

Adult↗

PubMed1982

Urine flow-dependence of theophylline renal clearance in man.

Theophylline renal clearance is highly dependent on urine flow rate and is neither concentration nor dose related. To examine the flow dependency, theophylline was administered in single doses (4.3 mg/kg to 8.6 mg/kg) to 14 volunteers. Seven of these volunteers participated in studies in which theophylline and metabolite concentrations were held constant at six different levels. Due to the diuretic effect of theophylline, its renal clearance contributed up to 70% of the time-averaged total clearance, dose/total area, in the first hour after a single dose. The contribution then dropped to 5% of the time-averaged total clearance when the normal urine flow rate was restored. As a consequence of extensive tubular reabsorption, the urine/plasma concentration ratio of theophylline varied with urine flow rate and approached the value of the unbound fraction in plasma. On assumption that the reabsorption is passive, a mathematical model was used to explain the urine flow dependence of reabsorption and, therefore, the renal clearance of theophylline.

Adult↗

PubMed1982

Nonlinear theophylline elimination.

Elimination kinetics of theophylline and its major metabolites were investigated in 14 healthy adults in single-dose studies and in a multiple-plateau study. The plasma concentrations of theophylline and the metabolites 3-methylxanthine (3-MX), 1-methyluric acid (1 MU), and 1,3-dimethyluric acid (13-MU) were monitored to about 0.020 mg/l and became convex descending at concentrations below 1 mg/l after single theophylline doses. Renal clearance values of 3-MX, 1-MU, and 13-MU were 12.0 +/- 1.3 l/hr, 22.5 +/-1.5 l/hr, and 22.6 +/- 1.6 l/hr. Metabolite formation of the three metabolites followed Michaelis-Menten kinetics and became capacity limited within the therapeutic range of theophylline. The apparent Michaelis-Menten parameters for each metabolite formation step were obtained by computer fitting. For the formation of 3-MX. 1-MU, and 13-MU, the approximate mean maximal rate of formation of metabolite (Vmax) values were 5 mg/hr, 13 mg/hr, and 34 mg/hr and the apparent concentration of theophylline at which metabolite formation rate is half of Vmax values were 2.7 mg/l, 9.3 mg/l, and 14.2 mg/l. The elimination of each of the metabolites was rate limited by the elimination of theophylline. Concomitant measurement of theophylline urinary excretion rate showed the renal clearance of the drug to be highly dependent on urine flow. The initial renal clearance, elevated due to diuresis, and the distribution phase tended to counterbalance the saturable metabolic formation clearance after a single therapeutic dose. Therefore, plasma theophylline concentration decayed roughly in a log-linear fashion and the convex-descending curve, characterized by capacity-limited elimination kinetics, was observed only at lower concentrations.

Administration, Oral↗

PubMed1982

An automated HPLC assay for simultaneous quantitation of methylated xanthines and uric acids in urine.

To investigate the elimination kinetics of caffeine and its metabolites, as well as the interaction between them, an automated HPLC method is described. This method involves a single extraction procedure, followed by a gradient elution. Fourteen methylated xanthines and uric acids are well separated with an assay sensitivity of 1 microgram/ml when one-half ml of urine is used. The assay is highly selective, from endogenous compounds, and reproducible. This method is recommended for accurate pharmacokinetic studies.

Caffeine↗

PubMed1981

Metabolism of theophylline to caffeine in adults.

Caffeine and its major metabolite, paraxanthine, were observed in plasma following oral administration of theophylline in a multiple dose study. At steady state, plasma caffeine concentrations varied from 0.21 to 0.75 mg/L at plasma theophylline concentrations of 8.1 to 21.5 mg/L in four healthy subjects. About 6% of the theophylline dose was converted to caffeine, which is further metabolized to a series of degradation products, which can be measured after caffeine administration, accounted for the incomplete urinary recovery usually observed after theophylline administration.

Adult↗

PubMedDate not supplied

Preclinical safety profile of brimonidine.

Brimonidine is a selective alpha 2-adrenergic agonist developed for lowering intraocular pressure in glaucoma patients. Since brimonidine will be used in long-term theraphy, the safety of this drug is an important feature for its clinical success. Brimonidine has been evaluated in a number of safety studies using doses much greater than those in humans. In this paper chronic and carcinogenicity studies are presented. The results of the 6-month ocular/systemic study in rabbits and the 1-year ocular/systemic study in monkeys with 0.2, 0.5, and 0.8% brimonidine ophthalmic formulations showed no ocular or organ toxicity. The highest concentration of 0.8% used in rabbits and monkeys resulted in plasma drug concentrations of 95 (Cmax) and 10 (C2hr) times, respectively, higher than those seen in humans following topical dosing. Dose-related transient exaggerated pharmacologic effects of sedation were observed in the 1-year oral study in monkeys without any organ toxicity. The dose that elicited an apparent pharmacologic effect produced a plasma drug concentration that was approximately 115 times higher than that in humans. In 2-year carcinogenicity studies in mice and rats using doses that produced plasma concentrations 77 and 118 times, respectively, higher than those seen in humans, no oncogenic effect was observed. Based on the extensive safety research on brimonidine, it was concluded that this drug has an excellent safety profile.

Administration, Oral↗