Analysis of enterohepatic circulation of cefixime in rat by fast inverse Laplace transform (FILT)

The enterohepatic circulation of cefixime in rat was evaluated by a nonlinear least square analysis program, MULTI(FILT), into which the fast inverse Laplace transform (FILT) was incorporated. The plasma time course in the bile duct-cannulated rat exhibited a biexponential curve after the rapid iv administration of cefixime. Several pharmacokinetic models for the enterohepatic circulation were constructed based on the recirculatory concept and the Laplace-transformed equations corresponding to these models were derived by means of the method of transfer function. The transformed equations were simultaneously fitted to the time courses of plasma concentration in rats with laparotomy and with bile duct cannula. The optimum model was selected based on the Akaike's information criterion (AIC). The local moment characteristics for a single pass through enterohepatic circulation were further calculated from the time courses of both the plasma concentration and the amount excreted into the bile. The recovery ratio (F_c and the mean circulatory time (¯t_c through a single pass of enterohepatic circulation were estimated 27.9% and 1.07 hr, respectively. The recovery ratio (F_a and the mean absorption time (¯t_a for the absorption process from the intestinal tract into the systemic circulation were 68.3% and 0.0234 hr, respectively. The recovery ratio (F_b and the mean transit time (¯t_b)for the disposition process through the systemic circulation into the bile were 40.8% and 1.05hr, respectively.Notation A _i coefficient - a _i exponent - (s) Laplace transform of the time course of plasma following intravenous dose - (s) Laplace transform of the time course of plasma following oral administration dose - (s) Laplace transform of the time course of plasma concentration without EHC - CL_b clearance into the bile - CL¹ total clearance through the single EHC (=CL_b/F_b) - D_iv intravenous dose - D_po oral administration dose - F_a recovery (availability) from intestinal tract to systemic circulation - F_b recovery from systemic circulation to intestinal tract - F_a recovery from oral dose (absolute availability) - F_c recovery through a single pass of EHC - F_g recovery through the stomach - (s) transfer function corresponding to the process outside the body through the intestinal tract - (s) transfer function for oral dose - (s) transfer function through the systemic circulation into the bile - (s) transfer function for a single pass of EHC - (s) transfer function through the stomach - f_i(t) weight function for the processi - (s) Laplace transform off _t (t) - (s) transfer function corresponding to the recirculatory process - k_a absorption rate constant - s Laplace variable - mean transit time for the absorption process from the intestinal tract - _a mean transit time for oral dose (=MAT) - mean transit time for the disposition process in the body - mean transit time for a single pass of EHC - t ₀ gap time     

Two-compartment dispersion model for analysis of organ perfusion system of drugs by fast inverse laplace transform (FILT)

A dispersion model developed in Chromatographic theory is applied to the analysis of the elution profile in the liver perfusion system of experimental animals. The equation for the dispersion model with the linear nonequilibrium partition between the perfusate and an organ tissue is derived in the Laplace-transformed form, and the fast inverse Laplace transform (FILT) is introduced to the pharmacokinetic field for the manipulation of the transformed equation. By the analysis of the nonlinear least squares method associated with FILT, this model (two-compartment dispersion model) is compared to the model with equilibrium partition between the perfusate and the liver tissue (one-compartment dispersion model) for the outflow curves of ampicillin and oxacillin from the rat liver. The model estimation by Akaike's information criterion (AIC) suggests that the two-compartment dispersion model is more proper than the one-compartment dispersion model to mathematically describe the local disposition of these drugs in the perfusion system. The blood space in the liver, V_B, and the dispersion number D_N are estimated at 1.30 ml (±0.23 SD) and 0.051 (±0.023 SD), respectively, both of which are independent of the drugs. The efficiency number, R_N, of ampicillin is 0.044 (±0.049 SD) which is significantly smaller than 0.704 (±0.101 SD) of oxacillin. The parameters in the two-compartment dispersion model are correlated to the recovery ratio, F_H, mean transit time, ¯t_H, and the relative variance, ²/¯t_H ², of the elution profile of drugs from the rat liver.Notation A Cross-sectional area of the blood space - C(t, z) Concentration of drug (one-compartment dispersion model) - C(s, z) Laplace transform of C(t, z) - C ₁(t, z) Concentration of drug in blood space (two-compartment dispersion model) - C ₂(t, z) Concentration of drug in the liver tissue (two-compartment dispersion model) - C ₁ (s, z) Laplace transform ofC ₁(t, z) - D Axial or longitudinal dispersion coefficient - D _c(=D· A ²) Corrected dispersion coefficient - D _N Dispersion number - f _I(t) Input function with respect tot - f_I(z) Input function with respect toz - F_I(s) Laplace transform of f_I(t) - f_s(t) System weight function with respect tot - f_s(z) System weight function with respect to z - F_H Recovery ratio - k Partition ratio (distribution ratio) - k₁₂, k₂₁ Forward and backward partition rate constant in the central elimination two-compartment dispersion model - k ₁₂ ^p ,k ₂₁ ^p Forward and backward partition rate constant in the peripheral elimination two-compartment dispersion model - k_e Elimination (or irreversible transfer) rate constant - k _e ^p Elimination rate constant in peripheral elimination model - K_H Distribution constant - L Length of blood space in liver - M Amount of drug injected - m Coefficient related to the injected amount - p_h Mass transfer coefficient from perfusate to hepatic tissue - Q Flow rate of perfusate - R_N Efficiency number - s Laplace variable - t Time - ¯ t_H Mean transit time - Linear flow velocity of the perfusate - V _B(= L·A) Blood volume (sum of the sinusoid volume and the space of Disse) - v_h Apparent volume of distribution - V _H Anatomical volume of liver tissue - z Axial coordinate in the liver - (t) Delta function - Volume ratio of the anatomical liver tissue to the blood space - ² Variance of transit time - ²/¯t _H ² Relative dispersion to transit time - Partial derivatives     

A note on appropriate constraints on the initial input response when applying deconvolution

When deconvolution is employed to estimate cumulative input profiles, nonzero initial values may result unless certain constraints are imposed on the function used to approximate the input response c(t).It is shown that the initial value of the response to a nonimpulse input is zero, i.e., c(t₀)=0,where t₀ is the input lag time. If, in addition, the initial value of the impulse response is zero, i.e.,c (0)=0,then c(t₀)=0.Therefore, it is appropriate to impose the constraint c(t₀)=0in general and c(t₀)=0when c (0)=0if c(t)is the response to a nonimpulse input. The use of such constraints is demonstrated in an example where the cumulative in vivodissolution profile is estimated by deconvolution.     

Theoretical and computational basis for drug bioavailability determinations using pharmacological data. II. Drug input ⇄ response relationships

Mathematical expressions and approaches to the computation of rates and extents of drug bioavailability for implementation on analog and digital computers are derived. The equivalency of expressions derived on the basis of assuming compartment models to an approach based on using experimentally determined weighting functions is demonstrated. The relative merits of the two techniques are discussed: their application for use with temporal pharmacological data is emphasized. The applicability of the computational techniques to determining the availability of drugs at local sites of action (biophasic availability) and to computing preabsorptive drug release into the gastrointestinal contents (gastrointestinal bioavailability) is pointed out. An approach to computationally predicting in vivo blood level or pharmacological response vs. time profiles from in vitro dissolution testing results is presented and its limitations are discussed.Research supported by Food and Drug Administration Contract No. 73-23, Alcon Laboratories, and the Purdue Biomedical Engineering Center.     

Influence of Dose Range on Degree of Nonlinearity Detected in Dose-Proportionality Studies for Drugs with Saturable Elimination: Single-Dose and Steady-State Studies

Deviation from proportionality occurs when the ratio of area under the curve (AUC) values is not equal to the ratio of administered doses. The degree of nonlinearity (f _NL) can be quantitated as the ratio of AUCs divided by the ratio of doses. We explore positive deviation from proportionality (f _NL > 1) using the classical Michaelis–Menten model of nonlinear elimination after a single dose (n = 1) or at steady state (ss). The degree of nonlinearity is related to the ratio of the highest dose to the lowest dose (Rd = D _H/D _L): f _NL ⁿ⁼¹ = (2 + Rd · )/(2 + ), f _NL ^ss= (Rd · –1) /(Rd · –Rd), where is the ratio of the initial concentration after the lowest dose to the K _m ( = D _L/K _m · V) and is the ratio of the V _max to the average rate of input for the highest dose ( = V _max/F · D _H). From these relationships, we find that (1) for single-dose studies, K _m is the important Michaelis–Menten parameter, while V _max is important at steady state; (2) the degree of nonlinearity cannot exceed the ratio of doses in single-dose studies, and when doses in extreme excess of K _m· V are chosen, the degree of nonlinearity is equal to the dose range; and (3) at steady state, the degree of nonlinearity can exceed the ratio of doses and approaches infinity as the average input rate approaches V _max. Literature data (phenytoin and ethanol) support these findings. We conclude that the degree of nonlinearity is not a useful measure of nonlinearity in and of itself and propose percentage saturation as being more informative.     

Disposition kinetics in dogs of diethyldithiocarbamate,a metabolite of disulfiram

Following the intravenous infusion of sodium diethyldithiocarbamate to dogs, the disposition kinetics of diethyldithiocarbamate (DDC), a metabolite of disulfiram, were assessed. Approximately 27% of the administered dose was S-methylated, this process exhibiting a mean first-order rate constant of 0. 0569 min^–1 (t_1/2=12.2 min), while the remainder was eliminated by other routes having a rate constant of 0.148 min^–1 (t_1/2=4.68 min). The methyl diethyldithiocarbamate (MeDDC) formed from DDC showed an elimination rate constant of 0.0141 min^–1 (t_1/2=49.2 min). These observations are discussed in the light of previous investigations where the presence of MeDDC has rarely been sought or reported. A few comparisons with prior studies, in which DDC or disulfiram was administered, are made by retrospective kinetic evaluation of published data. The results are discussed in relation to the duration of action of disulfiram in man.Glossary A plasma concentration intercept at the cessation of infusion (mass/volume) - A _T simplifying constant (mass/volume/time) - AUC _M area under the plasma concentration-time curve for MeDDC (mass × time/volume) - b time variable; equalst during infusion, equalsT after the cessation of infusion - B plasma concentration intercept at the cessation of infusion (mass/volume) - B _T simplifying constant (mass/volume/time) - C _D plasma concentration of DDC at any timet (mass/volume) - C _M plasma concentration of MeDDC, expressed as DDC, at any timet (mass/volume) - C _T plasma concentration of total DDC, expressed as DDC, at any timet;C _T=C_D+C_M (mass/volume) - C _t plasma concentration of total DDC, expressed as DDC, at any timet (mass/volume) - Cl _D total body clearance of DDC (volume/time) - Cl _M total body clearance of MeDDC (volume/time) - DDC diethyldithiocarbamate - f fraction of DDC that is methylated;f=K _DM/K _D - K _A apparent first-order rate constant (reciprocal time) - K _B apparent first-order rate constant (reciprocal time) - K _D apparent first-order rate constant for the elimination of DDC by all routes (reciprocal time) - K _M apparent first-order rate constant for the elimination of MeDDC by all routes (reciprocal time) - K _DE apparent first-order rate constant for the elimination of DDC by all routes except methylation (reciprocal time) - K _DM apparent first-order rate constant for theS-methylation of DDC (reciprocal time) - MeDDC methyl diethyldithiocarbamate - NaDDC sodium diethyldithiocarbamate (trihydrate) - Q zero-order infusion rate constant (mass/time) - Q ₁ zero-order infusion rate constant for the faster of two consecutive infusions (mass/time) - Q ₂ zero-order infusion rate constant for the slower of two consecutive infusions (mass/time) - t elapsed time since dosing (e.g., infusion) commenced - t elapsed time since the cessation of infusion - T duration of infusion (time) - T ₁ duration of the faster of two consecutive infusions (time) - T ₂ total duration of infusion when two consecutive infusions are administered (time) - V _D apparent volume of distribution of DDC - V _M apparent volume of distribution of MeDDC This work was supported by the Atkinson Charitable Foundation (Toronto, Ontario, Canada) and the Non-Medical Use of Drugs Directorate, Health and Welfare Canada (Grant No. 1212-5-206).     

Bilateral intra-accumbens self-administration ofd-amphetamine: Antagonism with intra-accumbens SCH-23390 and sulpiride

The efficacy ofd-amphetamine to support a selective bilateral intra-accumbens self-administration response was examined. Bilateral intra-accumbens infusions ofd-amphetamine were made contingent upon the acquisition of a lever-pressing response. Two identical levers were available within the operant chamber. Depression of the drug lever resulted in the intra-accumbens delivery of 1 µgd-amphetamine; responses upon the second, control lever were recorded but had no programmed consequences. Animals were not primed with non-contingent infusions ofd-amphetamine at any time during these experiments. Nonetheless, animals readily acquired a selective response upon the drug lever. Removal of thed-amphetamine moiety from the infusate resulted in a large decline in responding, and the abolition of the selectivity of the response for the drug lever. Adulteration of the infusate with either the D₁ dopamine receptor antagonist SCH-23390 or the D₂ dopamine receptor antagonist sulpiride enhanced the rate of response selectively upon the drug lever. Reductions in the dose ofd-amphetamine also increased the rate of response. The effect of co-adulteration of the infusate with both SCH-23390 and sulpiride together was purely additive. The implications of these data for the methodology of intracranial drug self-administration, and the relationship between D₁ and D₂ dopamine receptors within the nucleus accumbens are discussed.     

Pharmacokinetics of sulfametopyrazine (Kelfizine W) effects of a single oral dose

Summary The pharmacokinetics of sulfametopyrazine were studied for seven days after a single oral dose of 2 g. in healthy volunteers in order to establish its chemotherapeutic value. — The appearance and disappearance of the drug in the plasma were evaluated both for compounds with a free amino group and for total sulphonamides. The half-life and absorption, distribution, elimination and excretion coefficients were calculated, as well as the concentrations in plasma water and interstitial fluid. The estimated drug concentrations in the urine agreed with those calculated from the excretion coefficients. — In all subjects at the end of the seventh day the concentrations in all body compartments of active compounds exceeded the minimum required for a therapeutic effect. The highest concentrations found in the urine were always significantly lower than the drug's basal solubility at pH 5, thus excluding any risk of crystalluria.Glossary of symbols total binding capacity of plasma proteins for SMP - Specific gravity of blood ( Bl), and interstitial fluid (IF) - minimum inhibitory concentration for bacterial growth. Evaluation of against E. coli or other pathogenic bacteria in a medium free of antagonists [29] - ratio of dose interval to half-life - dose interval - safety factor. Proportionality constant between andc _min for a therapeutic efficacy of 95 per cent - fraction of the administered drug absorbed from the depot (gastrointestinal tract etc.) - distribution coefficient with respect to the drug concentration in blood plasma (ml/g) - D* initial dose of the drug - D maintenance dose - M molecular weight of the drug (280) - G weight of subject (kg) - F area between time axis and concentration curve (plotted c' values) - t _50% apparent biological half-life - w ¹ water content of plasma (ml/ml) - p protein concentration of plasma (pBl), or interstitial fluid (pIF) (g/l) - c _IF concentration in the interstitial fluid - C ₀ concentration in plasma at zero time after i.v. administration - c ₁ ⁰ concentration in plasma after oral absorption extrapolated to zero time - c ₁ concentration in plasma water of the drug with free amino function - c _min minimum inhibitory concentration needed in plasma water (minimum therapeutic concentration) - k ₀₁ rate constant for absorption - k ₁ rate constant for absorption determined at timet; (similarlyk₂) - K total elimination coefficient - k _el rate constant for elimination - k _F rate constant for formation of metabolites - k _D excretion coefficient of SMP with free amino function - k _U coefficient of metabolite excretion - D ₀ quantity of SMP in the body at time zero - D _B quantity of SMP in the body at timet - D _U quantity of SMP excreted in the urine at timet - M _F quantity of metabolites formed at timet - M _B quantity of metabolites present in the body at timet - M _U quantity of metabolites excreted in the urine at timet - K dissociation constant for the sulphonamide-protein complex - notation for quantities related to drug concentrations in plasma, e.g. c (corresponding term without refer to plasma water)     

Milnacipran enhances the control of impulsive action by activating D1-like receptors in the infralimbic cortex

Rationale

Elevated impulsivity is often observed in patients with depression. We recently found that milnacipran, an antidepressant and a serotonin/noradrenaline reuptake inhibitor, could enhance impulse control in rats. However, the neural mechanisms underlying the effects of milnacipran on impulsive action remain unclear. Milnacipran increases not only extracellular serotonin and noradrenaline but also dopamine specifically in the medial prefrontal cortex, which is one of the brain regions responsible for impulsive action.

Objectives

Our goal was to identify whether D₁- and/or D₂-like receptors in the infralimbic cortex (IL), the ventral portion of the medial prefrontal cortex, mediates the milnacipran-enhanced impulse control in a three-choice serial reaction time task.

Methods

The rats were bilaterally injected with SCH23390, a selective D₁-like receptor antagonist (0.3 or 3 ng/side) or eticlopride, a selective D₂-like receptor antagonist (0.3 or 1 μg/side) into the IL after acute intraperitoneal administration of milnacipran (10 mg/kg).

Results

Intra-IL SCH23390 injections reversed the milnacipran-enhanced impulse control, whereas injections of eticlopride into the IL failed to block the effects of milnacipran on impulsive action.

Conclusions

This is the first report that demonstrates a critical role for D₁-like receptors of the IL in milnacipran-enhanced control of impulsive action.     

Comparison of four basic models of indirect pharmacodynamic responses

Four basic models for characterizing indirect pharmacodynamic responses after drug administration have been developed and compared. The models are based on drug effects (inhibition or stimulation) on the factors controlling either the input or the dissipation of drug response. Pharmacokinetic parameters of methylprednisolone were used to generate plasma concentration and response-time profiles using computer simulations. It was found that the responses produced showed a slow onset and a slow return to baseline. The time of maximal response was dependent on the model and dose. In each case, hysteresis plots showed that drug concentrations preceded the response. When the responses were fitted with pharmacodynamic models based on distribution to a hypothetical effect compartment, the resulting parameters were dose-dependent and inferred biological implausibility. Indirect response models must be treated as distinct from conventional pharmacodynamic models which assume direct action of drugs. The assumptions, equations, and data patterns for the four basic indirect response models provide a starting point for evaluation of pharmacologie effects where the site of action precedes or follows the measured response variable.Glossary C _e Drug concentration at the hypothetical effect site - C _p Plasma concentration of drug - C _p(T_max) Plasma concentration of drug at the time of maximal response - D Dose - EC ₅₀ Drug concentration producing 50% of maximum stimulation at effect site - E _max Maximum effect attributed to drug - E _o Baseline effect prior to drug administration - IC ₅₀ Drug concentration producing 50% of maximum inhibition at effect site - K _el First-order rate constant for drug elimination - K _eo First-order rate constant for drug loss from effect site - K _in Zero-order rate constant for production of drug response - K _out First-order rate constant for loss of drug response - n Sigmoidicity factor of the sigmoid E_max equation - R Response variable - R_max Maximal (or minimal) response - R_o Initial response (time zero) prior to drug administration - t time after drug administration - T Infusion time - T_max Time to reach maximum effect following drug administration - V Volume of distribution Supported in part by Grant No. 24211 from the National Institutes of General Medical Sciences, National Institutes of Health.     

Design,Development and Optimization of S (-) Atenolol Floating Sustained Release Matrix Tablets Using Surface Response Methodology

The objective of this present investigation was to develop and formulate floating sustained release matrix tablets of s (-) atenolol, by using different polymer combinations and filler, to optimize by using surface response methodology for different drug release variables and to evaluate the drug release pattern of the optimized product. Floating sustained release matrix tablets of various combinations were prepared with cellulose-based polymers: Hydroxypropyl methylcellulose, sodium bicarbonate as a gas generating agent, polyvinyl pyrrolidone as a binder and lactose monohydrate as filler. The 3² full factorial design was employed to investigate the effect of formulation variables on different properties of tablets applicable to floating lag time, buoyancy time, % drug release in 1 and 6 h (D_{1 h,}D_{6 h}) and time required to 90% drug release (t_90%). Significance of result was analyzed using analysis of non variance and P < 0.05 was considered statistically significant. S (-) atenolol floating sustained release matrix tablets followed the Higuchi drug release kinetics that indicates the release of drug follows anomalous (non-Fickian) diffusion mechanism. The developed floating sustained release matrix tablet of improved efficacy can perform therapeutically better than a conventional tablet.     

The effect of duration of intravenous infusion on maximum and threshold blood concentrations for drugs exhibiting biexponential elimination kinetics

The relationships among peak blood concentration (C _max), the time (t _D ) during which blood concentrations are maintained above the minimum effective concentration (C _min), and the duration of a constantrate intravenous infusion (T) of a drug exhibiting biexponential pharmacokinetics were simulated by digital computer using Newton iterative procedures. These simulations showed that, in contrast with our previous findings for drugs with monoexponential pharmacokinetics, the relationships are more complex due to the larger number of variables. Therefore, investigation of these relationships for biexponential drugs should be done on a drug by drug basis. Accordingly, meperidine and sulfamethoxazole were chosen as examples of drugs which exhibit biexponential kinetics and were used to determine what errors were involved in using the simpler guidelines for drugs which exhibit monoexponential kinetics as an approximation. These simulations showed the following. (a) The effect ofT onC _max may be adequately estimated by using the guidelines for monoexponential kinetics with the elimination half-life taken as provided that ₁ is 20 to 30 times ₁ and that theAUC of the distribution phase (i.e.,C _{1/ 1} comprises greater than about 20% of the totalAUC. (b) As with monoexponential drugs, it is possible to obtain a largert _D by infusing the dose compared to that obtained with a bolus, if the value ofC(0)/C _min>2.5. (c) Using the approximation of monoexponential pharmacokinetics to estimate the effect ofC ont _D will underestimate botht _D and the maximum infusion time, which will just attain theC _min unless theAUC of the distribution phase comprises only a very small proportion of the totalAUC. (d) The simulations with meperidine also showed that the nature of the relationship betweent _D andT varies depending on whetherC _min is maintained in the distribution phase or in both the distribution and elimination phases.     

Evidence for thromboxane receptor mediated contraction of guinea-pig and human airways in vitro by prostaglandin (PG) D2, 9α,11β-PGF2 and PGF2α

Summary The rank orders of potency of prostaglandin D₂, prostaglandin F₂, 9,11-prostaglandin F₂ and the stable thromboxane A₂ mimetics U-46619 and ONO-11113 were determined in guinea-pig trachea and human bronchus in vitro. In both tissues the thromboxane mimetics were markedly more potent than the other prostanoids with EC₅₀ values in the nanomolar range. The prostanoid antagonists BW-245C, EP-092 and GR-32191 attenuated the contractile responses to all of the prostanoid agonists and TXA₂ mimetics tested in guinea-pig tracheal spirals, although agonist selectivity was seen. Contractile responses to methacholine in the guinea-pig trachea were unaffected by any of the antagonists employed. BW-245C antagonised the effects of all prostanoid agonists tested in human bronchial spirals, the pA₂ values obtained were similar to those seen in the guinea-pig trachea when U-46619 and 9,11-PGF₂ were employed as the agonists. However, significant differences were found between the two tissues when PGD₂ and PGF₂. were tested against BW245C. EP-092 produced pA₂ values against prostanoid agonists in the human bronchus similar to those seen in the guinea-pig trachea, as did GR-32191. It is concluded that whilst the contractile responses of guinea-pig and human airways smooth muscle to prostaglandin D₂, and the other prostanoids are mediated predominantly via thromboxane (TP) receptors, it can be inferred that other receptor populations may contribute to the contractile response. The presence of these minor subpopulations may account for the agonist selectivity seen both within and between tissues from different species. Send offprint requests to: R. L. Featherstone at the above address     

Which form of erythromycin should be used to treat gastroparesis? A pharmacokinetic analysis

Background:

Erythromycin is a macrolide antibiotic that exhibits prokinetic effects. It has been shown to enhance antral contractility and accelerates gastric emptying rates, primarily by stimulating motilin receptors.

Aim:

To determine the optimal dosage form of erythromycin for use as a prokinetic agent.

Methods:

Eight normal volunteers and three patients with documented gastroparesis ingested 250 mg erythromycin in tablet, suspension and intravenous forms. Serum erythromycin levels were determined at frequent intervals. These data were plotted vs. time and analysed for lag time, time to maximum concentration (t_max), maximum concentration (C_max) and bioavailability (F).

Results:

The absorption kinetics of the erythromycin suspension was notable for short lag times and early t_max, while lag times and t_max were delayed with the tablet form. Median lag time was 15 min for the suspension vs. 90 min for the tablet (P < 0.005). Median t_max for the suspension was 45 min vs. 180 min for the tablet (P < 0.005). A non-significant decrease in F was seen with the suspension compared to the tablet (P = 0.12).

Conclusion:

Based on the kinetic data from this study, erythromycin suspension is the ideal dosage form for administration of this drug as a prokinetic agent.

     

Generalizations in linear pharmacokinetics using properties of certain classes of residence time distributions. I. Log-convex drug disposition curves

Introducing the phenomenoiogical concept of a time-varying fractional rate of elimination k_D(t)and applying the theory of lifetime distributions, implications of the log-convexity of drug disposition curves are examined and some important applications are described. Linear pharmacokinetic systems exhibiting a log-convex impulse response and satisfying the basic conditions underlying the noncompartmental approach have the following properties: (1) The time-varying volume of distribution V(t)increases, and consequently the fractional rate of elimination k_D(t)=CL/V(t)decreases monotonically. (2) The concentration-time curve and the time course of total amount of drug in the body, respectively, have an exponential tail [where V(t)approaches the equilibrium value V_Z].The relative dispersion of residence times (CV _D ² =VDRT/MDRT²)and the ratio V_ss/V_Z (V _ss is the volume of distribution at steady state) act as measures of departure from pure monoexponential decay (one-compartment behaviour). The role of the latter parameters as shape parameters of the curve that characterize the distributional properties of drugs is discussed. Upper and lower bounds of the time course of drug amount in the body are derived using the parameters MDRTand CV _D ² or _z (terminal exponential coefficient), respectively. This approach is also employed to construct upper bounds on the fractional error in AUCdetermination by numerical integration that is due to curve truncation. The significance of the fractional elimination rate concept as a unifying approach in interspecies pharmacokinetic scaling is pointed out. Some applications of the results are demonstrated, using digoxin data from the literature.     

Transport Mechanisms in Iontophoresis. I. A Theoretical Model for the Effect of Electroosmotic Flow on Flux Enhancement in Transdermal Iontophoresis

Bulk fluid flow or volume flow in the direction of counterion flow is a probable mechanism for enhanced flux of uncharged species by iontophoresis. Both the electrical volume force effect, resulting from the interaction of the ion atmosphere and the electric field, and an induced osmotic pressure effect produce volume flow in the same direction as counterion flow through the membrane. Since each of these effects is proportional to the membrane charge and the imposed electric field, we classify both as electroosmotic flow. This research develops a detailed theoretical model which allows the effect of volume flow on flux enhancement to be evaluated. A detailed theoretical result for the electroosmotic flow coefficient also results from the analysis. The model assumes that transport occurs in three types of aqueous pores: positively charged, neutral, and negatively charged. For hairless mouse skin (HMS), pore size, charge, and number are evaluated from transference number, volume flow, and electrical resistance data. The flux enhancement ratio is J ₁/J ₁ ^D= A _ii/[l –exp( –_i)], where i = pore type, and the summation runs over the three pore types. A _i is the area fraction of pore type i effective for transport; J ₁ and J ₁ ^D are flux of species 1 with and without the electric field, respectively; and i is given by _i = F(–/RT)[ z ₁ + (–z _m ⁱ )Bar _i ² C _m ⁱ(G _i + F)]. Here F = Faraday's constant; – = voltage drop; R = gas constant; T = absolute temperature; z _m ⁱ = charge of pore i; C _m ⁱ = charge concentration in membrane pore of radius, r _i; B is a known collection of constants; a is the Stokes radius of the transported solute; G _i, is a function of membrane charge and pore radius coming from the electrical volume force effect; and F is a function of membrane charge and ion mobility arising from the induced osmotic pressure effect. For transdermal iontophoresis, F <<G, and the induced osmotic pressure effect is not significant. Negative pores dominate electroosmotic flow and usually dominate flux enhancement. The term proportional to C _m ⁱ is the contribution of electroosmotic flow and will always increase the flux enhancement ratio for anodic delivery of a positively charged ion (z ₁ > 0) or a neutral species (z ₁ = 0) in a negatively charged pore. The theoretical results are consistent with data in the literature.     

Characterization of a novel 5-HT4 receptor antagonist of the azabicycloalkyl benzimidazolone class: DAU 6285

Summary Three chemical classes of serotonin 5-HT₄ receptor agonists have been identified so far: 5-substituted indoles (e.g. 5-HT), benzamides (e.g. renzapride) and benzimidazolones (e.g. BIMU 8). In a search for 5-HT₄ receptor antagonists, we have discovered that the benzimidazolone derivative DAU 6285 (for structure see text), is 3–5 times more potent than tropisetron in blocking 5-HT, renzapride and BIMU 8 induced stimulation of adenylate cyclase activity in mouse embryo colliculi neurons. Schild plot analysis yielded K_i values of 220, 181 and 255 nmol/l, respectively. In addition, DAU 6285 showed poor activity as a 5-HT₃ receptor ligand with respect to tropisetron, as demonstrated by in vitro binding studies (K_i, 322 vs 2.8 nmol/l) and by its antagonistic activity in the Bezold-Jarisch reflex test (ID₅₀, 231 vs 0.5 g/kg, i.v.). No significant binding (K_i>10 mol/l) of DAU 6285 to serotonergic 5-HT_1A, 5-HT_1B, 5-HT_1C, 5-HT_1D, and 5-HT₂ receptors as well as to adrenergic ₁, ₂, dopaminergic D₁, D₂ or muscarinic M₁–M₃ receptor subtypes was found. The data indicate that DAU 6285 has a somewhat higher affinity than tropisetron for 5-HT₄ receptors, a property confirmed in functional tests, and much lower affinity than tropisetron for 5-HT₃ receptors. The compound represents a new interesting tool for investigating the pharmacological and physiological properties of 5-HT₄ receptors. Send offprint requests to A. Dumuis at the above address     

Demonstration of Ri-type adenosine receptors in bovine myocardium by radioligand binding

Summary Adenosine has been shown to have negative inotropic, chronotropic and dromotropic effects on the heart. The pharmacological profiles of these effects suggest that they are mediated via R_i (A₁) adenosine receptors, but a direct demonstration of these receptors is still missing. In the present study we report direct labelling of these receptors with (-)N⁶-[¹²⁵I]-p-hydroxyphenylisopropyladenosine ([¹²⁵I]HPIA). The radioligand bound in a saturable and reversible manner to a crude membrane preparation, the B _max-value was 30.5 fmol/mg protein and the K _D-value 1.1 nmol/l. A similar affinity of the ligand was obtained in kinetic and competition experiments. Competition experiments with a variety of adenosine analogues gave a pharmacological profile characteristic of R_i adenosine receptors with high affinities of N⁶-substituted derivatives and a marked stereospecificity for N⁶-phenylisopropyladenosine (PIA). Purification of the membrane preparation by density gradient centrifugation resulted in a 30-fold increase in the number of binding sites which was paralleled by a similar increase in the number of binding sites for [³H]ouabain. Guanine nucleotides decreased binding of [¹²⁵I]HPIA in a dose-dependent manner, but the IC₅₀-values were considerably higher than those reported in other tissues. Finally, binding of [¹²⁵I]HPIA appeared to be entropy-driven which has been shown to be characteristic of agonist binding to R_i adenosine receptors. These results suggest the presence of R_i adenosine receptors in ventricular myocardium which may be responsible for the mediation of the effects of adenosine and its analogues.Abbreviations [¹²⁵I]HPIA (-)N⁶-[¹²⁵I]-p-hydroxyphenylisopropyladenosine - (-)IHPIA (-)N⁶-iodo-p-hydroxyphenylisopropyladenosine - (+)/(-)PIA (+)/(-)N⁶-phenylisopropyladenosine - CHA N⁶-cyclohexyladenosine - NECA 5-N-ethylcarboxamidoadenosine - App(NH)p 5-adenylylimidodiphosphate - Gpp(NH)p 5-guanylylimidodiphosphate     

Occupancy of dopamine D2 and D3 and serotonin 5-HT1A receptors by the novel antipsychotic drug candidate, cariprazine (RGH-188), in monkey brain measured using positron emission tomography

Rationale

Cariprazine is a novel antipsychotic drug candidate that exhibits high selectivity and affinity to dopamine D₃ and D₂ receptors and moderate affinity to serotonin 5-HT_1A receptors. Targeting receptors other than D₂ may provide a therapeutic benefit for both positive and negative symptoms associated with schizophrenia. Positron emission tomography (PET) can be used as a tool in drug development to assess the in vivo distribution and pharmacological properties of a drug.

Objectives

The objective of this study was to determine dopamine D₂/D₃ and serotonin 5-HT_1A receptor occupancy in monkey brain after the administration of cariprazine.

Methods

We examined three monkeys using the following PET radioligands: [¹¹C]MNPA (an agonist at D₂ and D₃ receptors), [¹¹C]raclopride (an antagonist at D₂ and D₃ receptors), and [¹¹C]WAY-100635 (an antagonist at 5-HT_1A receptors). During each experimental day, the first PET measurement was a baseline study, the second after a low dose of cariprazine, and the third after the administration of a high dose.

Results

We found that cariprazine occupied D₂/D₃ receptors in a dose-dependent and saturable manner, with the lowest dose occupying ~5% of receptors and the highest dose showing more than 90% occupancy. 5-HT_1A receptor occupancy was considerably lower compared with D₂/D₃ occupancy at the same doses, with a maximal value of ~30% for the raphe nuclei.

Conclusions

We conclude that cariprazine binds preferentially to dopamine D₂/D₃ rather than to serotonin 5-HT_1A receptors in monkey brain. These findings can be used to guide the selection of cariprazine dosing in humans.