Nonlinear Clearance Research Articles

Effect of Concomitant Artesunate Administration and Cytochrome P4502C8 Polymorphisms on the Pharmacokinetics of Amodiaquine in Ghanaian Children with Uncomplicated Malaria

Artesunate (AS) is used in combination with amodiaquine (AQ) as first-line treatment for uncomplicated malaria in many countries. We investigated the effect of concomitant AS administration on the pharmacokinetics of AQ and compared concentrations of desethylamodiaquine (DEAQ), the main metabolite of AQ, in plasma between patients with different variants of the cytochrome P4502C8 (CYP2C8) gene. A two-compartment model was fitted to 169 plasma DEAQ concentrations from 103 Ghanaian children aged 1 to 14 years with uncomplicated malaria treated either with AQ alone (n = 15) or with AS plus AQ (n = 88). The population clearance of DEAQ appeared to increase nonlinearly with body weight, and the central volume of distribution of DEAQ was higher (P < 0.001) in the AS-plus-AQ group than in the AQ-only group. The maximum plasma DEAQ concentration was higher (P < 0.001), and the population distribution half-life was shorter (P < 0.01), in the AQ-only group than in the AS-plus-AQ group. The total areas under the plasma DEAQ concentration-time curves (P = 0.68) and elimination half-lives (P = 0.39) were similar for the two groups. There was a high frequency (0.179) of the non-wild-type allele of CYP2C8, but no differences between CYP2C8 genotypes with regard to AQ efficacy or safety were evident. The sample size, however, was limited, so monitoring of AQ toxicity in the study area is still indicated. The nonlinear clearance of DEAQ and the wide variability in kinetic parameters have safety implications for weight-based dosing of higher-body-weight children with AQ. The pharmacokinetics of artemisinin combination therapies should be studied in malaria patients, because the rapid parasite clearance caused by the artemisinin may affect the kinetics of the partner drug and the combination.

Nonlinear robustness analysis of flight control laws for highly augmented aircraft

In this paper, a novel hybrid optimisation algorithm is applied to the problem of analysing the robustness of a nonlinear flight control law in the presence of multiple variations in key aircraft parameters over continuous regions of the flight envelope. The analysis employs a typical nonlinear clearance criterion used by the European aerospace industry together with a simulation model of a high performance aircraft with a full authority control law which is gain scheduled over the flight envelope. The hybrid algorithm incorporates global (differential evolution) and local (sequential quadratic programming) optimisation algorithms to improve convergence properties and reduce computational overheads. The proposed approach is shown to have the potential to significantly improve both the reliability and efficiency of the industrial flight clearance process.

Population Pharmacokinetics Meta-Analysis of Recombinant Human Erythropoietin in Healthy Subjects

The aim of this analysis was to develop a population pharmacokinetic model to describe the pharmacokinetics of recombinant human erythropoietin (rHuEPO) in healthy subjects, after intravenous and subcutaneous administration over a wide dose range, and to examine the influence of demographic characteristics and other covariates on the pharmacokinetic parameters of rHuEPO. Erythropoietin serum concentration data were available from 16 studies comprising 49 healthy subjects who received rHuEPO intravenous doses from 10 to 300 IU/kg, 427 healthy subjects who received rHuEPO subcutaneous doses from 1 to 2400 IU/kg, and 57 healthy subjects who received placebo and where endogenous erythropoietin concentrations were measured. Different pharmacokinetic models were fitted to the dataset using nonlinear mixed-effects modeling software (NONMEM, Version V, Level 1). Several patient covariates were tested in order to quantify the effect on rHuEPO pharmacokinetic parameters. Model evaluation was examined using a posterior predictive check. Erythropoietin showed a diurnal baseline variation of +/-20%, described with a dual cosine model. Disposition was described with a two-compartment model with a small volume of distribution (6L) and parallel linear and nonlinear clearance. Total clearance varied between 0.3 and 0.9 L/h over the concentration range studied. A dual absorption model was used to characterise the rHuEPO absorption from the subcutaneous formulation and consisted of a faster pathway described as a sequential zero- and first-order absorption process and a parallel slower pathway characterised as a zero-order process. The bioavailability of subcutaneous rHuEPO increased from 30% at low doses to 71% at the highest dose of 160 kIU and was described using a hyperbolic model. The most important covariate effects were a decrease in the first-order absorption rate constant (k(a)) with increasing age, an increase in subcutaneous bioavailability with increasing baseline haemoglobin, and a decrease in bioavailability with increasing bodyweight. A posterior predictive check showed no systematic deviation of the simulated data from the observed values. The population pharmacokinetic model developed is suitable to describe the pharmacokinetic behaviour of rHuEPO after intravenous and subcutaneous administration in healthy subjects, over a wide dose range.

WORST-CASE ANALYSIS OF FLIGHT CONTROL LAWS FOR RE-ENTRY VEHICLES

This paper reports results of a joint study between ESA, DEIMOS Space S.L. and the University of Leicester on the robustness analysis of flight control laws for future hypersonic re-entry vehicles. We apply a novel hybridised version of the deterministic global optimisation algorithm, DIviding RECTangles (DIRECT), to perform worst-case analysis of a nonlinear-dynamic inversion (NDI) flight control law for a highly-detailed simulation model of a hypersonic re-entry vehicle. Nonlinear clearance criteria widely used in the European aerospace industry for the clearance of flight control laws for highly manoeuvrable aircraft are developed and applied in the context of the re-entry vehicle flight control problem. The proposed approach is shown to have the potential to improve significantly both the reliability and efficiency of the flight clearance process for future re-entry vehicles.

Pharmacokinetics and bioavailability of the isoflavone biochanin A in rats

Biochanin A (BCA) is a dietary isoflavone present in legumes, most notably red clover, and in many herbal dietary supplements. BCA has been reported to have chemopreventive properties and is metabolized to the isoflavone genistein (GEN), BCA conjugates, and GEN conjugates. The metabolites may contribute to the chemopreventive effects of BCA. The absorption, metabolism, and disposition of BCA have not been determined in rats. Our objective was to evaluate the pharmacokinetics and metabolism of BCA in rats. Male Sprague-Dawley rats were administered BCA by intravenous injection (1 and 5 mg/kg), by intraperitoneal injection (5 and 50 mg/kg), and orally (5 and 50 mg/kg). Plasma and bile samples were enzymatically hydrolyzed in vitro to determine conjugate concentrations for BCA and GEN. Equilibrium dialysis was used to determine protein binding. The BCA and GEN concentrations in plasma, urine, and bile were determined by liquid chromatography-tandem mass spectrometry (LC/MS/MS). The pharmacokinetic parameters of BCA were analyzed by noncompartmental analysis. Significant levels of BCA conjugates and GEN conjugates were detected in plasma and bile. Both BCA and GEN were found to have a high clearance and a large apparent volume of distribution; the bioavailability of both was poor (<4%). Reentry peaks were evident after oral administration of both BCA and GEN, suggesting enterohepatic cycling. The free fraction of BCA in rat plasma was 1.5%. A 2-compartment model that included both linear and nonlinear clearance terms and enterohepatic recirculation best described the plasma data. This represents the first evaluation of the dose-dependent pharmacokinetics and metabolism of BCA in rats.

A Semi-Physiological Population Pharmacokinetic Model Describing the Non-linear Disposition of Indisulam

The pharmacokinetic profile of the anti-cancer agent indisulam is non-linear. In addition to non-linear clearance, this may partially be explained by saturable distribution to red blood cells and saturable plasma protein binding. The aims of this study were to develop a semi-physiological population pharmacokinetic model of indisulam and to examine the impact of protein binding and distribution to red blood cells. Indisulam concentrations in plasma, plasma ultrafiltrate and in red blood cells from multiple phase I studies in Caucasian and Japanese patients were used to develop a pharmacokinetic model using NONMEM. This model comprised four physiological compartments: plasma, red blood cells, interstitial fluid and tissue. A simulation study was performed to examine the contribution of physiological processes in indisulam pharmacokinetics. Plasma albumin concentrations were predictive for the maximal protein binding capacity and considerably influenced total plasma concentrations of indisulam, whereas free plasma concentrations remained relatively unaffected. The maximal specific red blood cell binding capacity was 64.0 ( +/-5.9) mg/L and corresponded to the typical red blood cell carbonic anhydrase concentration. Simulation studies demonstrated that the hematocrit does not have a clinically relevant impact on indisulam disposition. This semi-physiological model allowed adequate prediction of the time profiles of indisulam concentrations in all monitored compartments for a large range of dose levels and several treatment regimens. The model has elucidated the mechanism and the role of saturable plasma protein binding and saturable distribution to red blood cells in indisulam pharmacokinetics and provides a basis for rationale PK-PD relationships.

ROBUSTNESS ANALYSIS OF NONLINEAR FLIGHT CONTROL LAWS OVER CONTINUOUS REGIONS OF THE FLIGHT ENVELOPE

In this paper, a hybrid global/local optimisation algorithm is developed and applied to the problem of analysing the robustness of a nonlinear flight control law over continuous regions of the flight envelope. The analysis employs a typical nonlinear clearance criterion used by the European aerospace industry together with a simulation model of a high performance aircraft with a full authority control law which is gain scheduled over the flight envelope. The flexibility of global optimisation methods is exploited to allow for clearance of the flight control law over continuous regions of the flight envelope in the presence of multiple continuous variations in key aircraft parameters. Convergence properties of the optimisation algorithm are improved by incorporating local gradient-based optimisation via a hybrid switching scheme.

The Population Pharmacokinetics of Citalopram After Deliberate Self-Poisoning: A Bayesian Approach

Defining the pharmacokinetics of drugs in overdose is complicated. Deliberate self-poisoning is generally impulsive and associated with poor accuracy in dose history. In addition, early blood samples are rarely collected to characterize the whole plasma-concentration time profile and the effect of decontamination on the pharmacokinetics is uncertain. The aim of this study was to explore a fully Bayesian methodology for population pharmacokinetic analysis of data that arose from deliberate self-poisoning with citalopram. Prior information on the pharmacokinetic parameters was elicited from 14 published studies on citalopram when taken in therapeutic doses. The data set included concentration-time data from 53 patients studied after 63 citalopram overdose events (dose range: 20-1700 mg). Activated charcoal was administered between 0.5 and 4 h after 17 overdose events. The clinical investigator graded the veracity of the patients' dosing history on a 5-point ordinal scale. Inclusion of informative priors stabilised the pharmacokinetic model and the population mean values could be estimated well. There were no indications of non-linear clearance after excessive doses. The final model included an estimated uncertainty of the dose amount which in a simulation study was shown to not affect the model's ability to characterise the effects of activated charcoal. The effect of activated charcoal on clearance and bioavailability was pronounced and resulted in a 72% increase and 22% decrease, respectively. These findings suggest charcoal administration is potentially beneficial after citalopram overdose. The methodology explored seems promising for exploring the dose-exposure relationship in the toxicological settings.

The absolute oral bioavailability (BA) of 150-mg and bioequivalence (BE) of six 25- and one 150-mg erlotinib (E) tablets, a small molecule inhibitor of the epidermal growth factor receptor (EGFR), in healthy volunteers

3163 Background: Single agent E (Tarceva, OSI Pharmaceuticals) produced a survival benefit in patients with locally advanced or metastatic NSCLC after failing at least one prior chemotherapy. The objectives of this study were to: 1) determine if a single dose of six 25-mg oral tablets are bioequivalent to a single 150-mg erlotinib oral tablet, and 2) determine the absolute oral BA of the 150-mg oral tablets in healthy volunteers. Methods: Adult subjects were assigned to 1 of 2 study arms (A or B): Arm A (n = 42) received a single E dose of six 25-mg tablets followed by one 150-mg tablet after a 14-day washout period. Arm B (n = 20) received E as a single 25-mg IV infusion given over 30 minutes followed by a single 150-mg tablet after a 14-day washout period. All oral doses were following an overnight fast. Non-compartmental analysis (NCA) was used to determine BA and BE. Once nonlinear clearance (CL) was observed in Arm B, a subsequent BA analysis was performed using a 2-compartment nonlinear model in NONMEM with the POSTHOC option. Results: The ratio of geometric means for AUCinf and Cmax following administration of six 25-mg tablets and one 150-mg tablet, were 1.00 (90% CI, 0.96–1.05) and 0.95 (90% CI, 0.88–1.04), respectively; indicating bioequivalence. With NCA, BA was >100% due to nonlinearity in CL. When analyzed using the 2-compartment nonlinear model, the predicted bioavailability (F) was 59% (95% C.I. 55%, 63%). A greater exposure to E was observed in female subjects (n=23) as compared to male subjects (n=19) in Arm A. Conclusions: E is well absorbed following oral administration, with a bioavailability of 59%, with six 25-mg tablets of E showing bioequivalency to a single 150-mg tablet. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Hoffmann-La Roche, OSI Genentech, OSI

HYBRID OPTIMISATION SCHEMES FOR THE CLEARANCE OF FLIGHT CONTROL LAWS

The application of two evolutionary optimisation schemes to the problem of flight clearance of nonlinear control laws for highly augmented aircraft is described. Hybrid versions of both schemes incorporating local gradient-based optimisation are also developed and evaluated. Comparisons of computational complexity and global convergence are conducted by checking for violations of a nonlinear clearance criterion for a detailed simulation model of a high performance aircraft with a full authority flight control law. The recently introduced differential evolution approach, when appropriately augmented with local optimisation methods, is shown to have significant potential for improving the reliability and efficiency of the current industrial flight clearance process.

Safety, Pharmacokinetics, and Activity of ABX-EGF, a Fully Human Anti–Epidermal Growth Factor Receptor Monoclonal Antibody in Patients With Metastatic Renal Cell Cancer

To determine the antitumor activity of ABX-EGF, a fully human monoclonal antibody to the epidermal growth factor receptor (EGFr), in previously treated patients with metastatic renal cell carcinoma, and to characterize its toxicity, immunogenicity, pharmacokinetics, and pharmacodynamics. The antitumor activity, as well as the toxicity, pharmacokinetics, pharmacodynamics, and immunogenicity of ABX-EGF, were assessed. Eighty-eight patients were treated with ABX-EGF doses of 1.0, 1.5, 2.0, or 2.5 mg/kg weekly with no loading dose. EGFr immunostaining was performed on 76 tumor biopsy specimens (86%), and 69 (91%) scored positive. Major responses occurred in three patients, and two patients had minor responses. Forty-four patients (50%) also had stable disease at their first 8-week assessment, and the median progression-free survival (PFS) was 100 days (95% CI, 58 to 140 days). Low hemoglobin and high alkaline phosphatase predicted for short PFS. The principal toxicity, an acneiform rash, occurred in 68%, 95%, 87%, and 100% of patients who received at least three doses of ABX-EGF at 1.0, 1.5, 2.0, and 2.5 mg/kg/wk, respectively. A trend indicated that the severity of the rash may relate to PFS. No human antihuman antibodies were detected. ABX-EGF pharmacokinetics fit a model that incorporated both linear and saturable EGFr-mediated clearance mechanisms, and interindividual variability was low. At 2.5 mg/kg/wk, ABX-EGF concentrations throughout treatment exceeded those estimated to saturate nonlinear clearance and inhibit xenograft growth by 90%. ABX-EGF was generally well tolerated. The objective response rate was low in previously treated patients with metastatic renal cell carcinoma. Although skin rash may be a pharmacodynamic marker of drug action, its potential as a surrogate marker of clinical benefit requires further evaluation.

Urinary excretion: does it accurately reflect relative differences in bioavailability/systemic exposure when renal clearance is nonlinear?

The purpose of this study was to assess the influence of nonlinear renal clearance on the ability of urinary excretion data to accurately determine relative differences in systemic exposure and bioavailability. Serum concentration and urinary excretion-time profiles were simulated assuming an open one-compartmental model with first-order absorption, linear nonrenal clearance, and either linear or nonlinear renal clearance (saturable secretion). Renal clearance comprised 5% or 95% of total clearance. Doses were varied over a 100-fold range (10-fold decrease/increase from the reference dose). Relative systemic exposures were based on the ratios of AUC and C(max) and the corresponding ratios of cumulative amount excreted in urine (A(e)) and the maximum urinary excretion rate. Relative bioavailability was based on the ratios of A(e) and the test to reference dose (D(ratio)). When renal clearance was linear and urinary excretion data were used to assess relative systemic exposure and relative bioavailability, no significant errors in accuracy were observed. However, when renal clearance was nonlinear, errors in the accuracy of estimation of relative bioavailability (Clr =5% only) and relative systemic exposure ranged from -53% to +125%; minimal error in accuracy existed in the estimation of relative bioavailability when Clr = 95% (-3% to +6%). Prior to the use of urinary excretion data to assess relative systemic exposure or bioavailability, the relationship between serum concentration and renal clearance should be established.

Population pharmacokinetics of sibrotuzumab, a novel therapeutic monoclonal antibody, in cancer patients.

Population pharmacokinetics of sibrotuzumab, a humanized monoclonal antibody directed against fibroblast activation protein, were determined after multiple intravenous infusions of dosages ranging from 5 mg/m(2) to an absolute dose of 100 mg, in patients with advanced or metastatic carcinoma. In total, 1844 serum concentrations from 60 patients in three Phase I and II clinical studies were analyzed. The structural model incorporated two disposition compartments and two parallel elimination pathways from the central compartment, one linear and one nonlinear. Finally estimated pharmacokinetic parameters (%RSE) were: linear clearance CLL 22.1 ml/h (9.6), central distribution volume V1 4.13l (3.7), peripheral volume V2 3.19l (8.8), inter-compartmental clearance Q 37.6 ml/h (9.6); for the nonlinear clearance Vmax was 0.0338 mg/h (25) and Km 0.219 microg/ml (57). At serum concentrations between approximately 20 ng/ml and 7 microg/ml, the effect of the nonlinear clearance on pharmacokinetics was marked. Only at >7 microg/ml did CLL dominate overall clearance. Interindividual variability was 57% for CLL, 20% for V1 and V2, and 29% for Vmax and was larger than the inter-occasional variability of 13%. Of the many investigated patient covariates, only body weight was found to contribute to the population model. It significantly affected CLL, V1, V2 and Vmax resulting in marked differences in the model-predicted concentration-time profiles after multiple dosing in patients with low and high body weights. In conclusion, a robust population pharmacokinetic model was developed and evaluated for sibrotuzumab, which identified a possible need to consider body weight when designing dosage regimen for future clinical cancer trials.

Lack of Whole-body Pharmacokinetic Differences of Halothane Enantiomers in the Rat

Halothane is made and used as a racemate (an equimolar mixture of R- and S- enantiomers). This study was initiated to determine whether there were demonstrable enantiomeric differences in the whole-body pharmacokinetics of halothane that might have significance for studies in which racemate is used. Adult male Wistar rats were exposed to halothane vaporized in the atmosphere of a closed constant volume chamber supplied with O2 commensurate with CO2 production. Concentrations of halothane enantiomers were measured by a specific gas chromatography-mass spectrometry method. Experiments were performed at four initial concentrations of halothane (0.1%, 0.5%, 1.0%, and 1.5% vol/vol). Enantiomeric differences in whole-body pharmacokinetics were assessed indirectly from the relative chamber atmosphere concentrations of halothane enantiomers. Concentrations of halothane decreased biphasically. The initial more rapid decrease was interpreted as incorporating absorption, distribution, and clearance; the slower decrease was interpreted as principally incorporating metabolic clearance. The ratio of concentrations of the two halothane enantiomers and of the ratios of the respective areas under the concentration-time curves remained constant without differing from unity at any time at any concentration of halothane. The dose-normalized areas under the concentration-time curves for the concentrations 0.1%, 0.5%, and 1.0% did not differ; that for 1.5% was significantly greater, suggesting nonlinear clearance, but the values did not differ significantly between enantiomers at any concentration. As there were no significant differences in concentrations of the two enantiomers in the chamber atmosphere, enantioselectivity was not demonstrated in the whole-body pharmacokinetics of halothane.

Analysis of nonlinear hepatic clearance of a cyclopentapeptide, BQ-123, with the multiple indicator dilution method using the dispersion model.

To bridge in vitro, in situ and in vivo kinetic analyses of the hepatic clearance of a cyclopentapeptide, BQ-123, by using dispersion models that assume nonlinear pharmacokinetics. Rat livers were perfused by the multiple indicator dilution method with doses of BQ-123 ranging from 1-1000 microg. The outflow dilution curves were fitted to a two-compartment dispersion model that was solved numerically by the finite difference method. Further, in vivo plasma concentrations of BQ-123 after bolus injection were analyzed with a hybrid physiological model that incorporates the hepatic dispersion model. The calculated Michaelis-Menten constants (Km = 12.0 microM, Vmax = 321 pmol/min/10(6) cells, P(dif) = 1.2 microl/min/10(6) cells) were comparable to those obtained previously from the in vitro isolated hepatocyte experiment (Km = 9.5 microM, Vmax = 517 pmol/min/l0(6) cells, P(dif) = 1.1 microl/min/10(6) cells). The plasma concentrations of BQ-123 at doses of 1-25 mg/kg were explained well by the hybrid physiological model. These results suggest that carrier-mediated transport on the sinusoidal membrane was responsible for the in vivo hepatic elimination of BQ-123.

Enhancement of oral bioavailability of phenytoin by esterification, and in vitro hydrolytic characteristics of prodrugs

To improve the oral absorbability of phenytoin (DPH), prodrugs of DPH with a small acyl substituent, N-carboethoxy- and N-carboisopropoxy-DPH (PT-1 and PT-2, respectively), were synthesized and bioavailabilities of them were evaluated after oral administration in rats, compared to that of DPH dosed. The prodrugs were rapidly hydrolyzed in the intestinal fluid, intestinal mucosa, liver homogenates and plasma of rats, the plasma giving the highest hydrolytic activity. Two different eliminations of DPH, slow and rapid, were observed after intravenous and oral administrations of prodrugs. The bioavailabilities of DPH after oral administration at a dose of 25 mg/kg of PT-1 and PT-2 (DPH equivalent), increased to approximately 8.5- and 6.0-fold for PT-1 and PT-2 (rapid elimination group) or 3.0- and 3.0-fold (slow elimination group), respectively, compared to those after dosing of DPH. The plasma levels of DPH converted from PT-2 dosed were lower, but more sustained in slow elimination groups than those from PT-1. The normalized AUC values after oral dosing of prodrugs at a dose of 50 mg/kg were increased dramatically, compared to those at a dose of 25 mg/kg, suggesting non-linear clearance at a high dose. In order to clarify the mechanism for preponderance of intestinal absorption of the prodrugs, concentrations of parent drug and prodrug were measured in intestinal mucosa after a single oral dosing of 50 mg/kg (DPH equivalent). Upon the administration of PT-1 and PT-2, greater amounts of DPH, in comparison with those after dosing of DPH, and small amounts of intact prodrugs were detected in the duodenal and jejunal mucosa. These data indicated that these prodrugs was subjected to the extensive intestinal absorption compared to DPH, giving comparatively high plasma levels. Therefore, PT-1 and PT-2 will be useful prodrugs as an orally applicable form. In particular, PT-2 seems to serve as a benign prodrug with the intention of improving the absorption of DPH.

Non-linear renal and biliary clearances of antiviral polyoxometalates in rats.

The polyoxometalates, JM 1591 (K12H2[P2W12O48].24 H2O), JM 1596 (K10[P2W18Zn4(H2O)2O68].20 H2O), and JM 2820 ([Me3NH]8[Si2W18Nb6O77]) have been shown to have potent activity against HIV-1 and HIV-2. The pharmacokinetics of JM 1591, JM 1596 and JM 2820 after intravenous administration of 50 mg/kg were investigated in rats. Renal and biliary clearances of the three compounds were found to be dependent on unbound plasma polyoxometalate concentration. Computer modeling was performed by fitting nonlinear pharmacokinetic models simultaneously to unbound plasma concentration, urinary excretion rate and biliary excretion rate versus time data. The renal clearances of JM 1591 and JM 2820 were described by glomerular filtration, saturated active tubular secretion at all plasma concentrations observed and saturable active tubular reabsorption. The urinary excretion of JM 1596 was characterized by glomerular filtration, saturable active tubular secretion and apparent linear reabsorption. Biliary clearances of all three polyoxometalates were described by a Michaelis-Menten function.

Relationship between the phasic period of interdigestive migrating contraction and the systemic bioavailability of acetaminophen in dogs.

The relationships of the phasic period of interdigestive migrating contraction to gastrointestinal (GI) transit of drugs and their oral absorption were investigated in mongrel dogs by simultaneous oral dosing of acetaminophen (AAP) and salicylazosulfapyridine (SASP) at the starting points of the phase I and phase III periods of gastric contractions. Strain-gauge force transducers were surgically sutured onto the serosa of the GI tracts in the dogs to measure the interdigestive migrating contractions. The mean absorption time of AAP and the time for the first appearance of sulfapyridine (a bacterial metabolite of SASP in the colon) in plasma were used as the indices of gastric emptying time (GET) and small intestinal transit time (SITT), respectively. In individual dogs, the GET and the SITT at phase I showed a clear delay in comparison with those at phase III. For AAP used as a marker compound here, the systemic bioavailability after oral dosing to intact beagle dogs at doses of 3, 10, and 20 mg/kg was about 55, 63, and 79%, suggesting that AAP undergoes a non-linear hepatic clearance. At a dose of AAP 20 mg/kg, the systemic bioavailability of AAP was 100% in the case of dosing at phase III, but was reduced by half when dosing at phase I. These results indicate that, in oral dosing, the transit of drugs through the GI tract was clearly affected by the phases of gastric contractions.(ABSTRACT TRUNCATED AT 250 WORDS)

The bioavailability and nonlinear clearance of (-)-carbovir in the rat.

The pharmacokinetics and bioavailability of (+/-)-carbovir, a carbocyclic nucleoside active against human immunodeficiency virus, have been described previously. To determine the bioavailability of (-)-carbovir, the biologically active enantiomer, four male Sprague-Dawley rats received 18 mg/kg of (-)-carbovir through the jugular vein and 54 mg/kg orally. Following the pilot studies, five rats were randomly assigned to receive (-)-carbovir in a three-way crossover design as either a single 18-mg/kg iv bolus, a single 54-mg/kg oral dose, or a single iv infusion of 18 mg/kg to achieve a target steady-state concentration (Css) of 1 micrograms/ml, the peak concentration after an oral dose. Blood and urine samples were analyzed by an improved ion-paired reversed-phase HPLC method with fluorescence detection. Blood concentrations of (-)-carbovir declined in a biphasic manner after the iv bolus dose. The terminal half-life was 116 and 106 min after the iv bolus and oral dose, respectively. The blood/plasma distribution ratio was approximately 1.0 in the range of 1 to 10 micrograms/ml of (-)-carbovir in blood. The free fraction in serum was concentration dependent. Significant differences in the renal, nonrenal, and total-body clearances after the iv bolus and iv infusion suggested nonlinear elimination of (-)-carbovir. The oral bioavailabilities derived from blood data were significantly different when the iv bolus was used as a reference rather than the iv infusion. However, the bioavailabilities were not significantly different when the total urinary excretion of unchanged (-)-carbovir after iv bolus or infusion was used as a reference.(ABSTRACT TRUNCATED AT 250 WORDS)

Nonlinear pharmacokinetics and interconversion of prednisolone and prednisone in rats

The pharmacokinetics of prednisolone and prednisone were examined in 32 rats at four intravenous doses (5, 10, 25, and 50 mg/kg). Each rat was given one dose of either intravenous prednisolone or prednisone, and plasma concentrations of both compounds were measured by HPLC. Mammillary moment analysis showed the apparent clearance and volume of distribution of prednisolone and the apparent clearance of prednisone to be dose-dependent. Further diagnostic analysis using a linear interconversion model revealed modest interconversion between the two steroids and at least two saturable clearance processes: the conversion of prednisolone to prednisone and the irreversible elimination of prednisone. A comprehensive model which incorporates the nonlinear clearances of prednisolone and prednisone plus the additional feature of nonlinear tissue distribution of prednisolone was then constructed. Four differential equations describing the rate of change of each steroid in each compartment were used to numerically fit by nonlinear least squares analysis all plasma concentration-time profiles simultaneously. The final estimates from the full model only partly agreed with the results from the two moment analyses but confirmed the general structure of the model. The nonlinear tissue distribution of prednisolone was reinforced by assay of muscle tissue. This study demonstrates the utility of the model-building process where simpler models yield insights into more elaborate schemes with complex nonlinear features.