Ocular pharmacokinetics of a novel tetrahydroquinoline analog in rabbit: compartmental analysis and PK-PD evaluation

The elimination kinetics of the pharmacologically active compound 1-ethyl-6-fluoro-1,2,3,4-tetrahydroquinoline (MC4) were characterized along with pharmacodynamic (PD) measurements. Four compartmental models based on ocular anatomy, physiology, and possible absorption and disposition pathways were proposed to model the pharmacokinetic (PK) data in WinNonlin and the best model was chosen based on statistical and goodness-of-fit criteria. A three-compartment physiologic-based PK model with a bidirectional transfer between cornea and aqueous humor and a unidirectional transfer between aqueous humor and iris-ciliary body best described the data. The ocular PD parameters, maximum effect attributed to drug (E(max)) and drug concentration which produces 50% of maximum effect (EC(50)), were estimated with change in intraocular pressure (ΔIOP) as the effect (PD response) in the effect compartment model (PK-PD link model) using aqueous humor concentration-time and ΔIOP-time profiles. The link model better described the effect compartment concentrations than a simple E(max) model that used iris-ciliary body concentration-time data, indicating that there is an apparent temporal displacement between aqueous humor concentration (plasma/central compartment equivalent) and pharmacological effect. A physiologically plausible value of 0.0159 min(-1) was obtained for the drug elimination rate constant (k(eo)) from the effect site to account for equilibration time in the biophase. Hysteresis was observed for the iris-ciliary body, aqueous humor drug concentrations, and effect data, further confirming the utility of the link model to describe the PD of MC4.     

Ocular hypotensive action of a novel tetrahydroquinoline analog in rabbit: physicochemical evaluation

Four new molecular entities, N-ethyl-1,4-benzoxazine (MC1), 1-ethyl-6-hydroxymethyl-1,2,3,4-tetrahydroquinoline (MC2), (R,S)-1-ethyl-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (MC3), and 1-ethyl-6-fluoro-1,2,3,4-tetrahydroquinoline MC4, based on the primary pharmacophore 1-ethyl-1,2,3,4-tetrahydroquinoline, were synthesized and tested for their physicochemical properties and pharmacological activities. The ocular hypotensive action was measured as percent intraocular pressure (%IOP) reduction, following topical administration in rabbit IOP recovery rate assay in vivo. The results were 4.8%, 14%, 4.5%, and 33% reduction for MC1, MC2, MC3, and MC4, respectively, with MC4 being the only statistically significant potent compound. The physicochemical properties such as solubility, distribution coefficient, and pKa were then determined in order to explain their pharmacological activities or lack thereof. MC4, the active compound, showed the highest solubility in pH 7.4 buffer, and in conjunction with ionization and distribution coefficient values, is expected to easily penetrate through the lipophilic corneal epithelium in comparison with the other compounds. Although the in vivo potency of MC4 can be attributed at least in part to its optimum physicochemical properties, it is important to note that differences in the receptor binding/potency, pharmacokinetic properties, and transporter interaction can also play a role in explaining the biological activity.     

Ocular disposition, pharmacokinetics, efficacy and safety of nanoparticle-formulated ophthalmic drugs

Ophthalmic drugs are delivered to ocular tissues predominantly via relatively simple formulations, such as topically dosed water-soluble drug solutions and water-insoluble drug suspensions in ointments. An ideal topical drug delivery system should possess certain desirable properties, such as good corneal and conjunctival penetration, prolonged precorneal residence time, easy instillation, non-irritative and comfortable to minimize lachrymation and reflex blinking, and appropriate rheological properties. In general, ocular efficacy is closely related to ocular drug bioavailability, which may be enhanced by increasing corneal drug penetration and prolonging precorneal drug residence time. To improve ocular bioavailability of topically dosed ophthalmic drugs, a variety of ocular drug delivery systems, such as hydrogels, microparticles, nanoparticles, microemulsions, liposomes and collagen shields, have been designed and investigated. These newer systems may, to some extent, control drug release and maintain therapeutic levels in ocular tissues over a prolonged period of time. This review focuses on the in vitro, ex vivo and in vivo studies of ophthalmic drugs formulated in nanoparticles published over the past two decades. The progress and development issues relating to ocular disposition, pharmacokinetics, efficacy and safety of the nanoparticle-formulated ophthalmic drugs are specifically addressed. Information and discussions summarized in this review are helpful for pharmaceutical scientists to develop better ophthalmic therapeutics.     

Ocular absorption and disposition of phenylephrine and phenylephrine oxazolidine

The ocular bioavailability of phenylephrine oxazolidine (PO), a prodrug intended for rapid corneal penetration, was micronized and suspended in sesame oil (1 and 10 per cent) and compared in bioavailability to phenylephrine HC1 (PE) dissolved (10 per cent) in a buffered (pH 5.75), viscous (30 centipoise) vehicle. Cornea and aqueous humor of New Zealand rabbits were measured over time following 10 microliter instillation to the eye. Based upon AUC measurements, corneal and aqueous humor levels were approximately 6 and 8 times greater for 10 per cent PO versus 10 per cent PE, respectively. In addition, the ocular pharmacokinetic values were determined for PE applied in a constant concentration (1 per cent) to the cornea over 180 min to anesthetized rabbits. Cornea and aqueous humor were measured for drug content over time. Using moment analysis and an initial slope method, the absorption rate constant, ka, the steady state volume of distribution in the eye, Vss, and ocular clearance, Qe, were calculated. Values obtained for PE were 4.15 x 10(-5) min-1, 0.423 ml and 14.6 microliter min-1, respectively. The half-life for drug elimination ranged from 63-83 min depending on the tissue or route of administration.     

Characterization, pharmacokinetics and disposition of novel nanoscale preparations of paclitaxel

Polymeric nanoparticles (NPs) have great potential application in achieving targeted delivery of anticancer drugs. Paclitaxel (PTX) loaded NPs were developed using biodegradable methoxy poly (ethylene glycol)-poly (ε-caprolactone) (MPEG-PCL) diblock copolymer by solid dispersion technique without toxic organic solvent. The lyophilized powder has been stored at room temperature for more than six months and still unchanged. PTX-loaded MPEG-PCL nanoparticles (PTX-NPs) displayed that the highest drug loading of PTX was about 25.6% and entrapment efficiency was over 98%, and the optimized average diameter and polydispersity index (PDI) were about 27.6 ± 0.1 nm and 0.05, respectively. Moreover, experimental results shown PTX-NPs had sustained-release effects and its curve fitting followed the Higuchi model. The maximum tolerated dose (MTD) of PTX-NPs after single dose in Balb/c mice was above 80 mg PTX/kg body weight (b.w), which was 2.6-fold higher than that of Taxol(?) (30 mg PTX/kg b.w). The levels of PTX administrated PTX-NPs had obvious distinction to Taxol(?) in plasma, liver, spleen, kidneys, lungs, heart and tumor. Especially, the concentration of PTX in tumor administrated PTX-NPs was higher than administration of Taxol(?). All results suggested that we had contrived a simple, biodegradable, effective and controllable drug delivery system for paclitaxel.     

Ocular absorption of benzydamine by the rabbit

An aqueous solution of 0.15 per cent benzydamine hydrochloride, a non-steroidal anti-inflammatory drug, was applied to the rabbit eye. Following topical application to the cornea, the drug was soon detected in the aqueous fluid of the treated eye, whereas the plasma levels were negligible. The possibility that benzydamine can inhibit inflammatory processes in the eye without the risk of side-effects is discussed.     

Ocular pharmacokinetics and safety of ciclosporin, a novel topical treatment for dry eye

Ciclosporin is a potent immunomodulator that acts selectively and locally when administered at the ocular surface. 0.05% ciclosporin ophthalmic emulsion has recently been approved by the US FDA for treatment of keratoconjunctivitis sicca (KCS) [dry-eye disease]. After topical application, ciclosporin accumulates at the ocular surface and cornea, achieving concentrations (>/=0.236 microg/g) that are sufficient for immunomodulation. Very little drug penetrates through the ocular surface to intraocular tissues. Ciclosporin is not metabolised in rabbit or dog eyes and may not be prone to metabolism in human eyes. Cultured human corneal endothelial and stromal cells exposed to ciclosporin in vitro exhibited no adverse effects and only minor effects on DNA synthesis. No ocular or systemic toxicity was seen with long-term ocular administration of ciclosporin at concentrations up to 0.4%, given as many as six times daily for 6 months in rabbits and 1 year in dogs. Systemic blood ciclosporin concentration after ocular administration was extremely low or undetectable in rabbits, dogs and humans, obviating concerns about systemic toxicity. In 12-week and 1-year clinical safety studies in dry-eye patients, the most common adverse event associated with the ophthalmic use of ciclosporin emulsion was ocular burning. No serious drug-related adverse events occurred.These data from in vitro, nonclinical and clinical studies indicate effective topical delivery of ciclosporin to desired target tissues along with a favourable safety profile, making 0.05% ciclosporin ophthalmic emulsion a promising treatment for KCS.     

Ocular pharmacokinetics of calcium, chloride and sulphate ions after instillation in the rabbit

The ionic environment of the eye is involved in major biochemical processes which are essential for preserving the integrity of cornea and lens. The purpose of the present study was to determine the intra-ocular penetration and the pharmacokinetic parameters of calcium, chloride and sulphate ions in the cornea, iris-ciliary body (ICB) and lens, after administration by instillation in the rabbit eye. In order to extrapolate our results to the processes occurring in man, we followed a precise instillation protocol using a low volume (5 microliters) of 45Calcium, 36Chloride and 35Sulphate, which is less than the lacrimal volume determined during the palpebral closing and performing manual blinking at a frequency of 2 min-1. The results indicate an immediate trans-corneal permeability and a rapid ocular distribution of these ions. We observe that, relative to dose, an important percentage of calcium (67.20 per cent) was entrapped in the cornea; this parameter was less important for chloride (10.19 per cent) and for sulphate ions (3.25 per cent). These values are in agreement with those predicted theoretically for trans-corneal penetration by such compounds. On the other hand, the total degrees of penetration by chloride and sulphate ions in ICB (1.40 per cent and 0.90 per cent, respectively) and lens (0.35 per cent and 0.41 per cent, respectively) are quite similar. Calcium retention is much higher in these tissues (25.39 per cent in ICB and 16.03 per cent in lens).(ABSTRACT TRUNCATED AT 250 WORDS)     

Artesunate/dihydroartemisinin pharmacokinetics in acute falciparum malaria in pregnancy: absorption, bioavailability, disposition and disease effects

AIM

To determine if reported lower plasma concentrations of artemisinin derivatives for malaria in pregnancy result from reduced oral bioavailability, expanded volume of distribution or increased clearance.

METHODS

In a sequentially assigned crossover treatment study, pregnant women with uncomplicated falciparum malaria received i.v. artesunate (i.v. ARS) (4 mg kg⁻¹) on the first day and oral ARS (4 mg kg⁻¹) on the second, or, oral on the first and i.v. on the second, in both groups followed by oral ARS (4 mg kg⁻¹ day⁻¹) for 5 days. Plasma concentrations of ARS and dihyroartemisinin (DHA) were measured by liquid chromatography-mass-spectrometry on days 0, 1, 2 and 6. Controls were the same women restudied when healthy (3 months post partum).

RESULTS

I.v. ARS administration resulted in similar ARS and DHA pharmacokinetics in pregnant women with malaria (n = 20) and in controls (n = 14). Oral administration resulted in higher total drug exposure in pregnancy [AUC (95% CI) in (ng ml⁻¹ h)/(mg kg⁻¹)] of 55.1 (30.1, 100.0) vs. 26.5 (12.2, 54.3) for ARS, P = 0.002 and 673 (386, 1130) vs. 523 (351, 724) for DHA, P = 0.007. The corresponding median absolute oral bioavailability (F%) was 21.7 (12.6, 75.1) vs. 9.9 (6.0, 36.81) for ARS (P = 0.046) and 77.0 (42.2, 129) vs. 72.7 (42.0, 87.7) for DHA, P = 0.033. Total DHA exposure was lower at day 6 in pregnant women with malaria (P < 0.001) compared with day 0 or 1, but not in the controls (P = 0.084).

CONCLUSIONS

This study demonstrates the effects of malaria on oral ARS drug disposition are greater than those of pregnancy. This probably results from a disease related reduction in first pass metabolism. The data are reassuring regarding current dosing recommendations.     

Absorption, disposition and pharmacokinetics of nanoemulsions

Nanoemulsions are composed of nanoscale droplets of one immiscible liquid dispersed within another, which have been the focus of extensive research worldwide due to their solubilization and transportation capacity of both hydrophobic and hydrophilic active compounds with unique physical properties. In a broad sense, submicron-emulsion, microemulsion, self-microemulsifing drug delivery system, lipid emulsion and cholesterol-rich microemulsion (LDE) all belong to nanoemulsions. The review starts with a brief introduction to the definition, formulation rationale, and types of nanoemulaions, and focused on, by different administration routes such as the oral, intravenous, transdermal, ocular nasal and rectal routes, the absorption, disposition, pharmacokinetics properties of nanoemulsions.     

Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition

MDMA (3,4-methylenedioxymethamphetamine, ecstasy) is a widely misused psychostimulant drug abused among large segments of the young population. Pharmacologically it displays effects related to amphetamine-type drugs and a set of distinctive effects (closeness to others, facilitation to interpersonal relationship, and empathy) that have been named by some authors "entactogen" properties. MDMA is a potent releaser and/or reuptake inhibitor of presynaptic serotonin (5-HT), dopamine (DA), and norepinephrine (NE). These actions result from the interaction of MDMA with the membrane transporters involved in neurotransmitter reuptake and vesicular storage systems. The most frequent effects after MDMA/ecstasy administration are euphoria, well-being, happiness, stimulation, increased energy, extroversion, feeling close to others, increased empathy, increased sociability, enhanced mood, mild perceptual disturbances, changed perception of colors and sounds, somatic symptoms related to its cardiovascular and autonomic effects (blood pressure and heart rate increase, mydriasis), and moderate derealization but not hallucinations. Acute toxic effects are related to its pharmacologic actions. The serotonin syndrome (increased muscle rigidity, hyperreflexia, and hyperthermia), among others, is characteristic of acute toxicity episodes. MDMA metabolism is rather complex and includes 2 main metabolic pathways: (1) O-demethylenation followed by catechol-O-methyltransferase (COMT)-catalyzed methylation and/or glucuronide/sulfate conjugation; and (2) N-dealkylation, deamination, and oxidation to the corresponding benzoic acid derivatives conjugated with glycine. The fact that the polymorphic enzyme CYP2D6 partially regulates the O-demethylenation pathway prompted some expectations that subjects displaying the poor metabolizer phenotype may be at higher risk of acute toxicity episodes. In this metabolic pathway a mechanism-based inhibition of the enzyme operates because the formation of an enzyme-metabolite complex that renders all subjects, independently of genotype, phenotypically poor metabolizers after the administration of 2 consecutive doses. Therefore, the impact of CYP2D6 pharmacogenetics on acute toxicity is limited. One of the interesting features of MDMA metabolism is its potential involvement in the development of mid- to long-term neurotoxic effects as a result of progressive neurodegeneration of the serotonergic neurotransmission system.     

Metabolism, disposition, and pharmacokinetics of tracazolate in rat and dog

The metabolism, disposition, and pharmacokinetics of tracazolate, (4-butylamino-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester), a novel anxiolytic agent, were studied in rat and dog following single oral and iv doses. Although tracazolate exhibits very good absorption (greater than 80%) in both species, it is extensively metabolized, accounting for low bioavailability. Excretion of 14C was rapid, with the kidney being the major organ of excretion. Tracazolate was not detected in the urine after iv doses even though measurable levels were found in blood, suggesting reabsorption of the compound by the renal tubules. The logarithm of the blood drug concentration vs. time data for both species was best described by a three-compartment open model. Mean t1/2 (beta) for tracazolate in the rat and dog were 14 and 10 hr, respectively. The distribution of radioactivity in rats showed that the concentrations of 14C and 14C-tracazolate were greater in tissues than in blood. Tracazolate was the predominant radioactive compound in brain during the first 6 hr and in fat for 96 hr. The extent and decay of tracazolate in fat strongly suggest that this tissue contributes significantly towards the equilibrium of drug between "deep body compartments" and blood. The major metabolite in blood was de-esterified tracazolate (ICI-US 7773) and in brain the gamma-ketotracazolate (ICI-US 10052).     

Intestinal absorption and presystemic disposition of sildenafil citrate in the rabbit: evidence for site-dependent absorptive clearance

Sildenafil citrate is the first oral treatment for erectile dysfunction. Its oral bioavailability is about 40%. This research investigated the intestinal transport parameters of sildenafil citrate in rabbit using an in situ intestinal perfusion technique. This was studied in four different anatomical sites, namely duodenum, jejunoileum, ascending colon and rectum. The results revealed the highest absorptive clearance in the jejunoileum. The values of the permeability area product normalized to segment length (ml/min.cm) were 0.0101, 0.0063, 0.0059 and 0.0023 and those of the percentage absorbed were 68.0, 32.3, 23.0 and 5.0 in jejunoileum, duodenum, ascending colon and rectum, respectively. The values of the length (cm) required for complete absorption were 87.6, 137, 153 and 384 for each anatomical site in the same order. The absorptive clearance did not correlate with the net water flux in the four anatomical regions studied, indicating a mainly passive diffusion mechanism through a transcellular pathway. The plasma sildenafil concentrations achieved during intestinal perfusion experiments and sildenafil total body clearance in the rabbit were used to calculate the fraction of sildenafil that reached the systemic circulation relative to the amount that disappeared from the intestinal segment. Only 34% of sildenafil that disappeared from the intestinal segment appeared in the systemic circulation indicating that the presystemic elimination of sildenafil is 66%. These results confirm that the incomplete bioavailability of sildenafil is mainly due presystemic elimination.     

Absorption, disposition and pharmacokinetics of solid lipid nanoparticles

Solid lipid nanoparticles (SLNs) are primarily composed of solid lipids, which thus impart to them some of the fundamental properties of these lipids, including biocompatibility, biodegradability and low-toxicity. SLNs represent a unique class of colloidal drug delivery systems that possess the advantages of both the "soft" drug carriers such as emulsions and liposomes and polymeric nanoparticles. In this review, we will provide an overview on the absorption, disposition and pharmacokinetics of SLNs. The lipidic nature, as well as the relatively small particle size, of SLNs ensures sufficient affinity with the biomembranes, and results in improved absorption by either of the oral, transdermal, pulmonary, nasal, ocular, rectal or buccal route. One special aspect of oral SLNs is the enhanced lymphatic absorption by either the chylomicron-association pathway or the M cell uptaking pathway. Intravenous SLNs are predominantly uptaken by the liver or spleen following opsonization by the complementary system. Modification of SLN surface with PEGs chains will mask the hydrophobic surface and divert SLNs to non-hepatic and non-splenic organs, while ligand-modification will achieve active targeting to specific tissues or organs. Degradation of SLNs is primarily based on the degradation of the lipids themselves by lipase. Pharmacokinetics reflects the effect of the lipidic vehicles of SLNs on in vivo disposition of the loaded drugs.     

Absorption, pharmacokinetics and disposition of biodegradable nanoscale preparations

Nowadays, biodegradable nanoscale preparations such as liposomes, micelles, nanoparticles (NPs), and solid lipid nanoparticles (SLN) have attracted increasing attention from major researchers. This article aims to review the absorption, pharmacokinetics, distribution properties and toxicity of the above-mentioned nanoscale preparations and the relative methodology. It may be significant for successful use of more nanoscale preparations in clinical practice.     

The disposition and pharmacokinetics of alpidem, a new anxiolytic, in the rat.

The autoradiographic distribution, disposition, biliary excretion, and pharmacokinetics of alpidem in Sprague-Dawley rats were evaluated after iv or oral administration. Following i.v. administration, autoradiography showed that radioactivity was preferentially localized in lipid-rich tissues including central nervous system structures. After a 3-mg.kg-1 i.v. or oral dose of [14C]alpidem, more than 80% of the radioactivity were excreted in the feces over a 6-day period. Biliary excretion of radioactivity in vigile rats, about 74% of the dose over a 7-hr period after either iv or oral administration, showed that alpidem was well absorbed. The absolute bioavailability (13%) data indicated a high first-pass effect. Plasma pharmacokinetic parameters of alpidem were as follows: Vd = 5 liter.kg-1, Cl = 2.2 liter.h-1.kg-1, and terminal t 1/2 beta = 1.2-1.7 hr. Three metabolites with a pharmacological activity similar to that of alpidem were detected in plasma. They were eliminated from the central compartment with half-lives comparable to that of the parent drug. Alpidem crossed the blood-brain barrier following either i.v. or oral administration, resulting in cerebral levels 2.5 to 4 times greater than the plasma levels. Alpidem was eliminated from the central nervous system according a biphasic process with a t 1/2 alpha comparable in plasma and brain. Alpidem represented 94 and 63% of cerebral radioactivity 5 min after i.v. and oral administration, respectively. Two out of the three active plasma metabolites were detected in the brain.     

Quinidine pharmacokinetics in man: choice of a disposition model and absolute bioavailability studies

Parameters describing disposition and absolute oral bioavailability of quinidine were determined in ten normal male volunteers using a specific assay. Various models were compared for their ability to describe the experimental data. An intravenous quinidine gluconate and an oral quinidine sulfate solution were administered (3.74 mg/kg quinidine base). In three subjects the intravenous and oral studies were repeated. One-, two-, and three-compartment models with zero and first-order input were fitted to the plasma concentrations. The selection of the best model was made by the Akaike information criterion and by eye. After intravenous administration, plasma concentration-time curves could be adequately described by a two-compartment model. Mean disposition constants (+/- SD) were obtained from individualized fits (V1: 0.398 +/- 0.336 LITER/KG, Vdarea: 2.53 +/- 0.72 liter/kg, alpha: 0.316 +/- 0.294 min -1, beta: 0.00204 +/- 0.00262 min -1, k2: 0.0305 +/- 0.0101 min -1). A clearance of 4.9 +/- 1.5 ml/min/kg was observed. After oral administration, three-compartment models were needed to describe the observed data in some cases. Absorption was in most cases best described by a zero-order rather than by a first-order process. The time to peak concentration varied from 23 to 121 min, the lag time was always less than 3 min, and the mean elimination rate constant was 0.00171 min -1. The mean oral bioavailability of quinidine was 0.70 +/- 0.17.     

Quinidine pharmacokinetics in man: Choice of a disposition model and absolute bioavailability studies

Parameters describing disposition and absolute oral bioavailability of quinidine were determined in ten normal male volunteers using a specific assay. Various models were compared for their ability to describe the experimental data. An intravenous quinidine gluconate and an oral quinidine sulfate solution were administered (3.74 mg/kg quinidine base). In three subjects the intravenous and oral studies were repeated. One-, two-, and three-compartment models with zeroand first-order input were fitted to the plasma concentrations. The selection of the best model was made by the Akaike information criterion and by eye. After intravenous administration, plasma concentrationtime curves could be adequately described by a twocompartment model. Mean disposition constants (±SD) were obtained from individualized fits (V₁: 0.398 ±0.336 liter/kg, Vd_area: 2.53±0.72 liter/kg, : 0.316±0.294 min^–1, : 0.00204 ± 0.00262 min¹, k₂: 0.0305 ±0.010 min^–1). A clearance of 4.9 ±1.5 ml/min/kg was observed. After oral administration, threecompartment models were needed to describe the observed data in some cases. Absorption was in most cases best described by a zeroorder rather than by a firstorder process. The time to peak concentration varied from 23 to 121 min, the lag time was always less than 3 min, and the mean elimination rate constant was 0.00171 min^–1. The mean oral bioavailability of quinidine was 0.70 ±0.17.This study was supported by funds from Food and Drug Administration Contract No. 223-74-3145. T. W. G. acknowledges support from the Swiss National Science Foundation, N. H. G. H. received a NIH fellowship for training in Clinical Pharmacology (GM 00001).