A pharmacokinetic interpretation of increasing concentrations of DEHP in haemodialysed patients.

The degree of exposure to DEHP was assessed in 11 patients with chronic renal failure undergoing maintenance haemodialysis. The amount of DEHP leached from the dialyser during a 4-h dialysis session was estimated by monitoring the DEHP blood concentration using a HPLC method. When a patient undergoes a dialysis treatment, the concentration of di-2-ethylhexyl phthalate (DEHP) in venous blood is increased when the blood crosses through the dialysis apparatus. This increase may be explained either because DEHP is not extracted by the dialyser or because DEHP comes from the dialysis bath due to contact of blood against plasticized pipes. To explain the increasing concentration of DEHP during treatment of renal failure using plasticized tubing, we propose a pharmacokinetic compartmental model in order to fit raw data obtained from dialysed patients and to get the amount of DEHP which enters the body by AUC calculations. Results obtained after HPLC analysis show a high degree of interpatient variability in DEHP retained. This amount can reach a toxicity level because of repetitive dialysis treatments over prolonged periods of time. In the coming years, it seems necessary to reconsider the use of DEHP as a plasticizer in medical devices. Highly unacceptable amounts of DEHP leached during the dialysis session could be easily avoided by careful selection of haemodialysis tubing.

Concentration at steady-state after periodic and non-uniform administration of drug.

A two-compartment model, with absorption from the gut and elimination from both compartments, is considered in order to express the concentration at any time and at steady-state when a drug is administered repeatedly according to a dosing schedule non-uniformly distributed over a 24-h interval. A time-delay is included to take into account the drug crossing from the gut to the central compartment.

Consequence of equal absorption, distribution and/or elimination rate constants.

When fitting experimental data to an open one- or two-compartment model, with first order kinetics, it may happen that no optimized value is obtained for model parameters. Several authors pointed out that this case is especially encountered when absorption and elimination coefficients approach each other in a one-compartment model or when absorption and exponential elimination or distribution rate constants are equal in a two-compartment model. We analyze these situations of equal coefficients here. Firstly, dealing with a one-compartment model, we get the concentration in the central compartment after a single oral dose and after successive various doses at various times (first order kinetics). Secondly, dealing with a two-compartment model, also for single or successive various doses, the concentration is expressed when absorption and exponential elimination or distribution rate constants are equal. In all cases, the areas under concentration curves and the mean residence time of the drug are calculated even when cancellation of one exponential term occurs. Furthermore, the concentration at steady-state is taken into account.

A pharmacokinetic model for multiple sites discontinuous gastrointestinal absorption.

PURPOSE: To build a pharmacokinetic model taking into account a discontinuous absorption along the gut, from n successive sites, a non-absorbing intestinal segment being always in between two successive sites. To solve the mathematical model linked with the pharmacokinetic model to obtain the concentration and contribution of each site to absorption, area under curve and bioavailability. METHODS: Whatever the number n of sites, we obtained the Laplace transform of amounts of drug in each site, then plasma concentration, so that concentration or AUC were expressed analytically. When only two absorption sites are present, concentration is obtained from Heaviside's theorem; but for n> or =3, Bromwich's theorem is necessary, a pole being of the order of more than two. RESULTS: Simulations performed with data gathered from the literature allow to find, with n=2 sites, the particular case used for ranitinine and to show the efficacy of each site. For n=3 sites, real data exhibiting three peaks of various magnitude were fitted on our model. CONCLUSION: This general discontinuous oral absorption pharmacokinetic model may be taken as a possible tool to characterize each site of absorption and to estimate the area under curves or bioavailability.

Local identifiability for two and three-compartment pharmacokinetic models with time-lags.

In this paper, we show that time-lags between compartments in a 2 and 3 compartment pharmacokinetic model may be taken into account but that separate identification for model parameters and for time-lags would not be suitable. Furthermore, it may happen that a time-lag model is locally identifiable while the corresponding model without delay is not. For two-compartment delayed models, with only one observation, it is not necessary to have two different inputs contrary to the case without time-lag. Both the Laplace transformation and a Jacobian matrix are used in an identifiability study. For all two-compartment models we have investigated which kind of parameters or lags are identifiable from amount (Q) or concentration (C) measures.

Enterohepatic recirculation of the new antihypertensive drug UP 269-6 in humans. A possible model to account for multiple plasma peaks.

Following a single dose of a new antihypertensive drug, UP 269-6 (5-methyl-7-propyl-8-[(2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]-1,2,4-triazolo[1,5-c]pyrimidin-2(3H)-one, CAS 148504-51-2), to 12 healthy volunteers, the plasma levels showed at least two secondary peaks. To explain this observation, the data were fitted to a new compartmental model of enterohepatic recirculation, without using a numerical method. Most subjects exhibited two cycles of recirculation. The amount of drug involved in each recirculation was calculated and the AUCs compared. The drug showed high biliary excretion and reabsorption.

Minimal experimental requirements for structural identifiability in linear compartmental models. The software 'IDEXMIN'.

Identifiability is a structural property of compartmental systems and is of a great interest in the pharmacokinetic field. Preliminary testing for identifiability, independent of the detailed experimental data but based on the model used and the experimental schedule, enables the researcher to design precise and straightforward experiments which will lead to the structural identifiability of the system. A computer program for PC (denoted IDEXMIN) has been designed in order to test for identifiability in any n compartment system and, in the case of non-identifiability, to define the minimal experimental data required to enable the model to be identifiable. All identifiability calculations are based on the K matrix of Delforge. Commandability and controllability of a system are verified before testing for identifiability.

Estimation of the effective amount entering the body for drugs subject to enterohepatic recirculations.

A pharmacokinetic model is used to take into account multiple recirculations of drug occurring at various times after gall bladder emptying. If a dose D is initially administed, due to recirculation, an effective amount A* reaches the body. This value A* is expressed as a function of D and the model parameters, after oral administration or intravenous injection. Using areas under curves in two different situations, the reabsorption rate may be identified.

Evidence for a second site of absorption of veralipride in the human small intestine. Use of a new drug delivery telemetric shuttle.

A new telemetric shuttle was used to coadminister veralipride (CAS 66644-81-3) and veralipride-D3 in order to test the assumption that veralipride is absorbed at two sites of the small intestine. Two different pharmacokinetic approaches were used to interpret the obtained data. According to the results, the second site of absorption of veralipride is located at a distance corresponding to 2/3 of the total length of the small intestine.

Pharmacokinetic compartmental model with n sites of absorption along the gastrointestinal tract.

A double site of absorption model was previously proposed to depict the "double peak phenomenon" in plasma concentration observed after oral administration of veralipride. We intend to generalize this model to the case where the drug reaches not two but n (n > or = 2) successive absorption sites along the gastrointestinal tract. Fractions of dose absorbed in each site are given as well as the area under concentration curves related to the central compartment. The effect of the number of absorption sites on absorbed amounts, on area under the curves and bioavailability is taken into account. Furthermore, as an example, we give simulated plasma concentration curves for a three-absorption site model.

Effect of drug transit time between exchange locus with plasma and sampling site.

In pharmacokinetic models used to describe the behavior of drugs in living organisms, generally neither the amount of drug flowing in pipes between compartments nor the transfer delay between the plasma-lymph exchange areas and a site of measurement are taken into account. Several former publications dealt with exchanges between two or more different organs assuming that the blood flow was constant or that the variation of the lymphatic flow was negligible or noting that the amount of drug present in pipes was not easily taken into account. In this article, we deal with concentration in a site of interstitial exchanges with regard to concentration in a sampling site with a varying blood flow, assuming that the transit time depends both on the fluid flow and the path length through pipes. In all considered cases, the plasma concentration profile may be highly altered by a change in the flow rate.

Mean residence time in multicompartmental models with time delays.

Calculation of the mean residence time (MRT) of a drug in a stationary compartmental model is classically carried out from several expressions. Nevertheless, one or more time delays between compartments modify the mean residence times. It is the aim of this paper to propose a general method for MRT calculations, in any n-compartmental models which may include time delays. As examples, catenary and mammillary models are considered.

Drug recirculation model with multiple cycles occurring at unequal time intervals.

A pharmacokinetic model for enterohepatic recycling has been developed to take into account multiple recirculations likely to occur at various times after intravenous or subcutaneous injection, after infusion, or after a single oral administration of a drug. The times when the gall bladder empties, the duration of infusion and the number of recirculations may be arbitrarily chosen (for simulations) or computed (for optimization) to express the concentration in the central compartment at any time. Without a new theoretical calculation, the area under the concentration curve may be obtained as a function of the model parameters. As an example, the model is applied to an experimental case of four recirculations after oral administration and to a new drug data fitting.

The amount of drug remaining in the body at the time Tmax after simultaneous extravascular and intravenous administration.

When a drug is simultaneously given extravascularly and intravenously, the plasma concentration reaches a maximum at a time Tmax. The purpose of this paper is to get the amount of the drug remaining in the body at this time Tmax. Furthermore, mean residence time of the drug and the area under concentration curve are given.

Application of a pharmacokinetic model with multiple enterohepatic cycles to a new inotropic drug after infusion and oral administration.

A pharmacokinetic model with multiple, unequal, enterohepatic recirculations was developed to fit the experimental data of a new inotropic drug after intravenous infusion and oral administration. Optimized model parameters were used to derive theoretical values of the area under the curves of concentration versus time that were in good agreement with the experimental values.

Fraction of absorbed drug at the time of peak plasma concentration in an open one-compartment model after simultaneous oral and intravenous administration.

When a drug is simultaneously given orally and intravenously, the plasma concentration generally reaches a maximum. The purpose of this paper is to assess the extent of absorbed drug at the time Tmax.

Pharmacokinetic modeling of plasma and cerebrospinal fluid methotrexate after high-dose intravenous infusion in children.

A pharmacokinetic study was performed in plasma and cerebrospinal fluid (CSF) of patients suffering from brain tumors to describe the disposition of methotrexate. An open three-compartment model was developed to fit together the data obtained in plasma and CSF. The pharmacokinetic parameters obtained by the model agreed with those obtained with classical analysis and the fitting correctly depicted the plasma and CSF concentration decays. According to the results, such a model could be applied to other anticancer drugs.

Relationship between loading dose and infusion rate to achieve any fraction of the steady-state level in any compartment model.

When a drug is infused at a constant rate K0, the time necessary for the concentration to reach a satisfying threshold of effectiveness may be too long. To achieve this level faster, it is useful to give simultaneously a dose D, of the same drug by intravenous injection. This paper proposes the calculation, as a function of K0 and model parameters, of the loading dose D necessary to reach, in a time T, any fraction of the asymptotic value of the amount of drug in a compartment receiving a constant rate infusion, for any n-compartment model. As an example, the expression of D for mammillary and catenary pharmacokinetic models is derived.

Decrease in albendazole sulphonation during experimental fascioliasis in sheep.

1. The in vivo S-oxidation of albendazole was measured from the pharmacokinetic profile of albendazole sulphoxide and sulphone determined in young male sheep receiving oral albendazole (1.9 mg/kg). Studies were carried out before, and each month after, oral infestation by 150 metacercariae of Fasciola hepatica. 2. Parasitic pathology was ascertained by clinical observation of animals, and the increase in plasma antibodies directed against liver flukes. 3. Rate of conversion of sulphoxide to sulphone and rate of sulphone elimination, were respectively decreased by 47% and 87% at week 8 post-infection, whereas significant increases in the area under plasma sulphone concentrations versus time curve and mean residence time, occurred 4-12 weeks following the infestation. 4. A 58% decrease in albendazole sulphonation was demonstrated in liver microsomal preparations obtained from 8-week-infected sheep, while there was no change in the FAD-directed sulphoxidation of albendazole. 5. The transient impairment of albendazole sulphonation could be related to the decrease in liver microsomal cytochrome P450-dependent monooxygenases observed in sheep with a similar parasitic pathology.