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.     

Topical carbonic anhydrase inhibitors IV: Relationship between excised corneal permeability and pharmacokinetic factors

Ethoxzolamide (1) and two analogues, representing a hydroxyethoxy and a hydrogen substitution on the 6-position of the benzene ring (2 and 3), were applied to rabbit eyes using a topical infusion method designed to provide a constant rate into aqueous humor. Statistical-moment theory was applied to the topical infusion data to describe disposition of each compound within the rabbit eye. For each analogue, it was possible to compare the corneal absorption rate constant (ka), aqueous humor elimination rate constant (k10), disposition mean residence time (MRTd), apparent steady-state volume of distribution (Vdss), and total ocular clearance (Qe). In vivo ocular ka values were related to maximum in vitro corneal penetration rates determined across excised rabbit corneas. In particular, 2 had a much longer residence time and a slower clearance than 1 and 3, which may be responsible for its ability to lower intraocular pressure when dosed topically to the rabbit eye, whereas 1 and 3 show no activity.     

Pharmacokinetics and pharmacodynamics of topotecan in patients with advanced cancer.

Topotecan, a semisynthetic water-soluble analog of camptothecin, is the first topoisomerase I-directed drug to enter clinical trial in the United States in over 20 yr. In this study, 30-min infusions of topotecan were administered daily for 5 days every 3 weeks at doses ranging from 0.5 to 2.5 mg/m2. Topotecan is reversibly hydrolyzed in a pH-dependent reaction in aqueous solutions to the ring-open hydroxy acid. The disposition of the closed ring lactone has been studied in 26 patients, and the disposition of both lactone and hydroxy acid has been studied in 12 patients. The clearance rate for topotecan lactone was 1220 ml/min/m2, with a range of 300-4760 ml/min/m2. The clearance rate for total topotecan (lactone and hydroxy acid) was 493 ml/min/m2, with a range of 163-815 ml/min/m2. A model for the disposition of lactone and hydroxy acid incorporating both reversible hydrolysis and elimination was developed. We have shown that topotecan is partially hydrolyzed prior to administration in parenteral solutions, and that clearance of the parent compound proceeds in vivo by conversion to hydroxy acid and elimination. Renal clearance accounted for 30 +/- 18% of drug elimination in patients. The relationship between topotecan dose and myelotoxicity is well fit by a sigmoidal Emax model, as is the relationship between total topotecan area under the concentration-time curve and myelotoxicity. The disposition of topotecan was also studied in mice. The clearance rate for total topotecan in mice was 330 ml/min/m2 after administration of topotecan lactone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of Furegrelate After Oral Administration to Normal Humans

Furegrelate sodium is a thromboxane synthetase inhibitor with potential for the treatment of various diseases including hypertension, thrombosis, and renal disorders. The absorption and disposition of the parent drug in normal male volunteers have been studied after single- and multiple-dose oral administration. The results from the single-dose study indicate that furegrelate is rapidly absorbed, with a T _max of 1.0–1.7 hr, has an apparent terminal disposition rate constant of 0.12–0.17 hr^–1, and is eliminated primarily by the kidney, with 62–78% of the dose excreted as parent drug. After multiple-dose oral administration for 4.5 days using a b.i.d. dosing regimen, no apparent change in the absorption, disposition, and elimination kinetics is detected and only a slight potential for drug accumulation is observed.     

Percutaneous absorption and disposition of iodochlorhydroxyquin in dogs

The percutaneous absorption and disposition of iodochlorhydroxyquin (5-chloro-7-iodo-8-quinolinol; I) from a 3% cream were studied in five dogs over a 28-d topical treatment period. Plasma levels, determined by HPLC, were 0.275-0.525 microgram/mL. The steady-state elimination rate of total I in urine was 2.4-3.0 mg/d. The apparent elimination rate constant and half-life were 0.25 +/- 0.05 d-1 and 3.1 +/- 0.5 d, respectively. Greater than 50% of topically applied I was absorbed over 16 h. Occlusion of the skin without the drug indicated that the skin acted as a reservoir for the drug. Feces analysis for iodochlorhydroxyquin from one dog showed that 27.1 +/- 8.5 mg/d was eliminated via this route. Tissue levels of I 15 d after the 28-d topical treatment were 0.7 microgram/g of liver, 0.2 microgram/g of kidney, and 0.8 microgram/g of mesenteric fat. The apparent rate constants of plasma level decline after a 100-mg iv bolus dose of I were alpha = 3.9 h-1 and beta = 0.6 h-1. The urinary elimination after intravenous administration was biphasic. The rate constant for the slow elimination phase was 0.4 +/- 0.1 d-1, and the half-life was 2.0 +/- 0.5 d. The primary neurological symptoms observed during topical treatment were ataxia and hind limb paralysis. Microscopic examination revealed liver necrosis. A weight loss of 15.3 +/- 2.7% was also observed over the 28-d topical treatment period. The results indicate that significant percutaneous absorption of I occurs, and that chronic high-dose topical treatment may lead to toxicity.     

Modeling drug absorption from enteric-coated granules.

A system-approach-based method is proposed for modeling drug absorption from enteric-coated granules. This method was exemplified using enteric-coated granules of aspirin given to healthy subjects. Based on the results obtained, it can be concluded that absorption of salicylate from the granules can be sufficiently described using a first-order linear model with an absorption rate constant of salicylate similar to that reported for an aqueous solution of aspirin administered orally to healthy subjects. The method proposed in this study may contribute to the working library of modeling techniques in pharmacokinetics since it allows direct modeling of the drug absorption process and estimates the absorption rate constant of a drug when its behavior in the body is significantly influenced by a gastric emptying process. i.e., when the absorption rate constant of the drug cannot be estimated on the basis of its cumulative absorption-time profile.     

Theorems and implications of a model independent elimination/distribution function decomposition of linear and some nonlinear drug dispositions. I. Derivations and theoretical analysis

The approach presented enables a model independent representation of the pharmacokinetics of drugs with a liner disposition and some drugs with a nonlinear disposition. The approach is based on a decomposition of the drug disposition into an elimination function q(c) and a distribution function h(t). The q function represents the net effect of all disposition processes which work toward a reduction in the systemic drug level. The h function represents the net effect of all disposition processes which slow down the rate of decline of the systemic drug level by returning drug from the peripheral environment to the systemic circulation. Several theorems relating q and h to the drug disposition are presented which uniquely define these functions mathematically. The disposition decomposition is of particular significance in three main areas of pharmacokinetics: (1) evaluation of drug absorption, (2) drug level predictions including steady state predictions, (3) and elucidation of drug disposition kinetics. The practical significance of the decomposition method in these three areas is discussed, and various procedures for the application of the method are proposed. The decomposition method represents a model independent alternative to pharmacokinetic models such as linear compartmental models, the recirculation model, and some physiologic models. This also includes nonlinear forms of such models, as long as the nonlinearity is due to a central nonlinear elimination. The greatest promise and significance of the disposition decomposition approach appears to be its application to nonlinear pharmacokinetics. In contrast to linear pharmacokinetics the kinetic analysis in such cases has been limited to model dependent methods employing specific pharmacokinetic models, due to the lack of model independent alternatives. The novel development presented offers such alternatives. For some applications these alternatives appear more rational in the sense that the analysis becomes more general and objective and may be based on fewer assumptions.     

Ocular pharmacokinetics of a novel tetrahydroquinoline analog in rabbit: absorption, disposition, and non-compartmental analysis

The pharmacologically active compound (33% reduction in rabbit intraocular pressure recovery rate assay) 1-ethyl-6-fluoro-1,2,3,4-tetrahydroquinoline (MC4), which showed ocular hypotensive action and had optimum physicochemical properties, was characterized for its ocular absorption and distribution properties to better understand its in vivo potency in comparison with an inactive compound, N-ethyl-1,4-benzoxazine (MC1). Tissue distribution to various ocular tissues was determined after absorption by both corneal and conjunctival-scleral routes, following administration by the "topical infusion" technique. The rank order of penetration for both the compounds was cornea > iris-ciliary body > aqueous humor > lens > conjunctiva-sclera. Overall, MC4 had significantly higher concentrations than MC1 in various ocular tissues, but particularly in the iris-ciliary body, which is the site of action (biophase). Ocular disposition studies of the active compound MC4 were then conducted to characterize its elimination kinetics, and the pharmacokinetic parameters were determined by non-compartmental and moment analysis using equations specific to "topical infusion" technique: first-order absorption rate constant, 4.1 × 10(-4) min(-1) ; elimination rate constant, 0.012 min(-1) ; mean residence time, 39.6 min; steady-state volume of distribution, 0.721 mL; and aqueous humor ocular clearance, 8.44 μL/min. The results were consistent with the conclusion that MC4 is well absorbed and distributed to the active site.     

A method for calculating the mean absorption time of drugs undergoing reversible and first-pass metabolism

A method has been derived for calculating the mean absorption time of an oral drug and its interconversion metabolite which is generated from the drug systemically and presystemically. The method evolves from the convolution integral and requires plasma AUC and AUMC values after separate intravenous administration of the drug and its interconversion metabolite and oral administration of the drug. It can also be used to calculate the mean input time of a drug undergoing reversible metabolism and administered by any other extravascular route. Results of a simulation study using both errorless and errant data indicate that, when the absorption rate constant of a drug or its interconversion metabolite is not much larger than the apparent elimination rate constant, the proposed method performs satisfactorily. However, when the absorption rate constant of a drug or its interconversion metabolite is much larger than the apparent elimination rate constant, the proposed method appears to be inaccurate.     

Analysis program based on finite element method, MULTI(FEM), for evaluation of dose-dependent local disposition of drug in liver

A curve-fitting program based on the Finite Element Method, MULTI(FEM), was developed to model nonlinear local disposition of a drug in the liver under non-steady-state conditions. The program was written in FORTRAN on an IBM-compatible personal computer. The validity of MULTI(FEM) was confirmed by analyzing the outflow kinetics of oxacillin (a model drug) following a pulse input to isolated, perfused rat livers, according to both linear and nonlinear dispersion models. Four dose levels (300, 1000, 3000, and 5000 microg) of oxacillin were administered to observe the dose-dependency in the hepatic local disposition. First, the individual outflow time-profiles at the same dose were averaged, and the average time-profile was analyzed by MULTI(FEM) based on linear dispersion models to yield a single curve fit. The fitted parameters at each dose level were compared with parameters estimated using MULTI(FILT), a program based on fast inverse Laplace transform, to analyze linear pharmacokinetics. The estimated parameters by MULTI(FEM) were in good agreement with those by MULTI(FILT). The apparent elimination rate constant (ke) decreased with an increase in dose, whereas other parameters showed no discernible dependency on an increase of dose. Second, the average outflow time-profiles at the four dose levels were simultaneously analyzed by MULTI(FEM) based on dispersion models featuring Michaelis-Menten elimination. The outflow time-profiles of oxacillin were well approximated by a two-compartment dispersion model with central Michaelis-Menten elimination. The maximum elimination rate constant (Vmax) and the Michaelis constant (Km) were estimated to be 1520 microg/mL/min and 41.3 microg/mL, respectively. Thus, the capability of MULTI(FEM) was demonstrated in evaluating capacity-limited local disposition in the liver.     

Absorption and disposition characteristics of nitrofurantoin in dogs

This study reports the disposition kinetic properties of nitrofurantoin in dogs following single intravenous and oral administration of various formulations of nitrofurantoin. Also reported here is the effect of delaying gastric emptying by food and atropine on the absorption characteristics of nitrofurantoin. The drug absorption parameters calculated using a deconvolution computer program indicate that the rate and extent of enterohepatic recycling affects the elimination and absorption rate constants and thus confound the bioavailability calculations of nitrofurantoin, heretofore unrecognized in the literature. The plasma half-life following intravenous administration was 31 min (monoexponential equation) with little effect of enterohepatic recycling noted. Following oral administration, a biexponential equation with lag-time was used to fit the blood levels. The absorption half-lives were higher when nitrofurantoin was administered as a solid dosage form compared to a solution. The absorption half-lives following tablet administration ranged from 30 to 72 min and were not affected by food or atropine. The elimination half-lives following oral administration ranged from 19 to 87 min with significantly prolonged elimination when solid dosage forms were administered compared to solution. The extent of absorption ranged from 38 to 120 per cent. A direct correlation between the absorption and elimination half-life was established, indicating that increased biliary recycling direct affects the apparent disposition half-life. The three brands of nitrofurantoin tested for bioavailability showed that the use of blood levels without appropriate corrections for biliary recycling are not suitable for bioavailability testing of nitrofurantoin. The use of urinary excretion data in evaluating nitrofurantoin bioavailability is also questioned in the study.     

Biopharmaceutical evaluation of carprofen following single intravenous, oral, and rectal doses in dogs

Absorption and disposition characteristics of carprofen were compared in the dog after intravenous, oral, and rectal administrations. Rectal formulations included an aqueous solution and a suppository. Single doses of 100 mg carprofen were given in a cross-over design and plasma concentrations of unchanged drug were determined by HPLC. Plasma concentration-time profiles could be adequately described after intravenous and extravascular administrations by tri-and biexponential functions, respectively. After intravenous applications the basic disposition parameters could be determined: mean (+/- S.D.) elimination half-life was about 11.7 (+/- 3.1) h; volume of distribution ranged from 0.12 to 0.22 l kg-1 and total plasma clearance was about 0.017 +/- 0.003 l h kg-1. After oral dosing, carprofen was rapidly absorbed (time of maximum concentration: 0.83 +/- 0.61 h) and comparison with the intravenous solution indicated complete bioavailability. After rectal administration, the rate of absorption evaluated through tmax and calculation of mean absorption times was always slower than after oral dosing. Relative bioavailabilities of the drug from the suppository were about 20 per cent lower than from rectal solutions. No significant difference in rates of absorption of carprofen from rectal solution and suppository was seen; this allowed the conclusion that drug release from the semi-solid dosage form was not the rate-limiting step in carprofen absorption from the suppository. From the present study, it is concluded that rectal administration of carprofen offers an alternative to the oral route of drug intake.     

DEMONS—A NEW DECONVOLUTION METHOD FOR ESTIMATING DRUG ABSORBED AT DIFFERENT TIME INTERVALS AND/OR DRUG DISPOSITION MODEL PARAMETERS USING A MONOTONIC CUBIC SPLINE

DeMonS—a new numerical deconvolution method for estimating the amount of drug absorbed at different time intervals and/or drug disposition model parameters—is presented here. In DeMonS, the amount of drug absorbed at different time intervals and/or drug disposition model parameters are the unknown parameters to be calculated. The Fritsch–Butland non-decreasing cubic spline was constructed from the cumulative amount of drug absorbed–time data directly derived from the calculated amount of drug absorbed at different time intervals. The drug absorption rate, which is the derivative of this non-decreasing cubic spline, is therefore represented by a piecewise non-negative quadratic function. The drug concentrations were obtained by convoluting the drug absorption rate quadratic function with the drug disposition model function. The nonlinear optimization method with simple parameter bounds was used to estimate the optimal set of unknown parameters by minimizing the sum of squares of residuals between the observed and predicted drug concentrations. DeMonS has been applied to (i) the griseofulvin data for estimating drug absorbed at different time intervals when the drug disposition model parameters were determined separately from intravenous data, (ii) veralipride double-peak phenomenon data to estimate simultaneously the percentage of cumulative veralipride absorbed and the veralipride disposition model parameters without reference intravenous data, (iii) a comparative bioequivalence study of gastrointestinal therapeutic system (GITS) pseudoephedrine HCI (PeHCI) controlled-release oral dosage forms when the drug disposition model parameters were not available, and (iv) estimation of both drug disposition model parameters and the absorption rate of drug from Testoderm^® (testosterone transdermal system) in the presence of endogenous testosterone production. DeMonS was implemented using MATLAB^® and NAG^® MATLAB Toolbox, and is available for Windows 3.1. © 1997 John Wiley & Sons, Ltd.     

Paracetamol pharmacokinetics in thyroid disease

Summary The absorption, distribution and elimination of oral paracetamol have been studied in patients before and after treatment of thyrotoxicosis (n=7) and hypothyroidism (n=4). Absorption was faster in patients with untreated thyrotoxicosis than when subsequently euthyroid. The peak paracetamol concentration, however, was lower in thyrotoxic patients due to an apparent increase in the total body clearance and a shorter plasma half-life. Both absorption and elimination rates were reduced in hypothyroid patients, but were not significantly different from the euthyroid results. When estimated using a two compartment model the total volume of distribution and the hybrid distribution rate constants were unrelated to thyroid status, but the apparent volume of the central compartment was significantly greater in the thyrotoxic group. These changes in drug disposition may contribute to differences in drug response seen in thyroid disease.     

Drug absorption evaluation in the presence of changes in clearance: an algorithm and computer program for deconvolution with exact clearance correction

Most commonly drug absorption is evaluated with a reference dosing given on separate occasions. The assumption that no change in drug disposition is taking place between the drug administrations is often violated resulting in errors in the calculations. A novel deconvolution method is presented which exactly compensates for a change in drug clearance. The method is based on a model independent disposition decomposition-recomposition technique. The distribution function is obtained from an i.v. administration by disposition decomposition. This distribution function is assembled together with the elimination kinetics containing the perturbed clearance to construct the perturbed disposition function in the subsequent disposition recomposition operation. The perturbed absorption response is finally deconvolved using the corresponding perturbed disposition function. It is shown that the perturbed clearance can be obtained from the log-linear terminal disposition phase once the distribution function has been obtained from an i.v. administration. The proposed method is implemented in an algorithm and computer program DCONB and demonstrated using human cimetidine drug level data from an i.v. and oral administration. The usage of DCONB is identical to DECONV previously published. It requires only regular sums of exponentials to be fitted to drug level data. Such fittings are routinely done in pharmacokinetics thereby enabling DCONB to be implemented very simply.     

Novel method of calculating absolute bioavailability in nonlinear pharmacokinetics

Current methods of evaluating the bioavailability of drugs with nonlinear disposition kinetics are based on specific pharmacokinetic models in contrast to the more rational model independent (structureless) area under the curve (AUC) and deconvolution methods used in linear pharmacokinetics. A novel method of evaluating bioavailability is presented which applies to any nonlinear type of drug elimination, but is limited to drugs with a distribution phase which is short relative to the elimination phase. The method applies to drugs with autonomic disposition characterized by a rate of decline in the systemic drug level in the absence of drug input which depends only on the drug level, i.e., dC/dt = -q(C), where q can be any function dependent only on C and constant kinetic parameters. It is shown that the disposition function q(C) can be evaluated in an empirical fashion from elimination-phase data and that this function can be used to calculate the absolute bioavailability of autonomic, nonlinear drugs. Some preliminary results are presented to demonstrate the procedures involved in applying the method.     

The Area Function Method for Assessing the Drug Absorption Rate in Linear Systems with Zero-Order Input

A noncompartmental approach for determination of the apparent zero-order absorption rate constant (k ₀) has been developed. The procedure evolves from the convolution integral and requires individual oral-dose plasma concentration values and calculation of area intervals under the plasma concentration–time curves after intravenous administration. The proposed method was evaluated and compared with the Wagner–Nelson, Loo–Riegelman, deconvolution, nonlinear regression, and moment methods using errorless and errant simulation data for one- or two-compartment models. The area function method is generally equal to the best of these techniques (nonlinear regression) and superior to the weaker methods (moment, deconvolution, Loo–Riegelman), especially for errant two-compartment data. Coupled with a companion procedure for constructing fraction absorbed versus time plots and assessing first-order absorption rate constants, the area function methods offer direct and accurate means of discerning drug absorption kinetics without the need for assignment of a disposition model for drugs with linear elimination kinetics.     

Mechanistic studies on transcorneal permeation of pilocarpine.

The mechanism of corneal pilocarpine penetration was studied in the albino rabbit using radiochemical techniques. The apparent rate and extent of pilocarpine accumulation in the aqueous humor and the various cell layers of the cornea were determined for both intact and abraded eyes. For the first time, drug levels were monitored in the epithelium and stroma-endothelium of the intact cornea using a tissue-scraping technique. In addition, a new postinstillation rinsing method was devised to evaluate the rate of corneal uptake. The results demonstrate a dual role for the corneal epithelium, both as a barrier to drug penetration and as a reservoir for drug in the intact cornea. The transcorneal pilocarpine flux is slower than the data appear to indicate, and previous overestimates of the apparent absorption rate constant are due to parallel elimination processes occurring at the absorption site. Pharmacokinetic parameters were determined for each tissue to generate an overall mechanism for corneal permeation.     

The pharmacokinetics of yohimbine in man

Summary The kinetic disposition of yohimbine was examined in eight young male subjects following a single oral dose of 10 mg yohimbine hydrochloride. The drug was rapidly absorbed (absorption half-time 0.17±0.11 h) and rapidly eliminated from the plasma (elimination half-life 0.60±0.26 h). This clearance of yohimbine from plasma was constant over approximately 10 elimination half-lives, suggesting that distribution into a second pharmacokinetically distinct compartment was not responsible for the rapid decline in plasma yohimbine levels. Urinary excretion and the partitioning of the drug into red blood cells (RBC) was investigated. In the 24 h following oral administration of the drug, virtually no yohimbine was eliminated in the urine (0.35±0.50% of the administered dose). Furthermore, only 20% of blood-borne yohimbine was located in RBC. These results suggest that yohimbine is eliminated primarily through metabolism since the rapid plasma clearance of yohimbine was not the result of renal elimination or sequestration by RBC.     

A new approach to pharmacokinetic parameters: estimation of cefuroxime during haemodialysis

A linear three-compartment model is proposed as a means of estimating disposition and extracorporeal elimination pharmacokinetic parameters during haemodialysis. It was created by connecting a compartment, corresponding to the amount of drug present in the dialysis cell, to the central compartment of the standard two-compartment model from which elimination would normally take place. The transfer rate constants between the central compartment and the 'dialysis cell' and vice versa were given in terms of the plasma flow, central compartment volume, and volume of plasma contained in the dialysis cell, and thus cannot be considered to be independent parameters. The product of the rate constant for elimination from the dialysis cell, k30, and the plasma volume within the cell was used to quantify the extracorporeal elimination and termed intrinsic dialyser clearance, CLint,D. The model was used to interpret the plasma level curves obtained after administering 750 mg cefuroxime by IV bolus to a group of patients undergoing haemodialysis. The distribution parameters estimated by non-linear regression were similar to those given in the literature; however, in five of the twelve cases, no estimate of cefuroxime elimination from the central compartment (k10) could be derived. On the other hand, the estimates of the elimination rate constant (k30) from the deep peripheral compartment were greater than the values given in the literature, ranging from 50.6 h-1 to 151.0 h-1 and CLint,D ranging from 3.1 h-1 to 8.90 l h-1. The error in measuring the flow of plasma which reaches the dialyser, its influence upon the estimation of the model parameters and the relationship between the parameters themselves and those customarily used in the study of drug haemodialysis are all discussed.