Pharmacokinetics of chlorpheniramine after intravenous and oral administration in normal adults

Summary Plasma and urinary levels of chlorpheniramine (CPM) and its 2 demethylated metabolites were measured by HPLC after i.v. and oral dosing. In 5 mg (maleate) i.v. bolus studies in 2 subjects, plasma CPM levels were fitted to triexponential equations with terminal half-lives (t _1/2) of 23 and 22 h and area of 3.6 and 3.21/kg, respectively. Intravenous data predicted hepatic blood extraction ratios for the 2 subjects to be 0.06 and 0.07, respectively. Absolute bioavailability from oral solution (10 mg) was 59 and 34%, and from tablets (8 mg) 44 and 25%, respectively, indicating extensive gut first-pass metabolism. Mean t _1/2 from 7 oral fasting studies in 5 subjects was 28 h (19–43 h). Mean absorption lag time was 0.7 h (0.4–1.3 h), and mean peak time was 2.8 h (2–4 h). In 2 subjects, 6 mg solutions were given every 12 h for 9 doses; good correlation between single and multiple dose kinetics was found. Significant accumulation was demonstrated in simulation studies with frequent daily dosing. Estimated accumulation ratios vary from 4.1 to 9.4 (mean 6.5). The t _1/2 from urinary data (collected for 12 days) was consistent with plasma data. The above results suggest the need to reexamine the current practice of frequent daily dosing and the use of sustained or controlled release dosage forms of this drug. The possible cause of reduced plasma clearance of CPM in renal patients is discussed.     

Pharmacokinetics,bioavailability and tissue distribution of geniposide following intravenous and peroral administration to rats

In order to characterize the pharmacokinetics, bioavailability and tissue distribution of geniposide following intravenous and peroral administration to rats, a reliable gradient HPLC‐based method has been developed and validated. After p.o. administration of geniposide, the peak concentration of geniposide in plasma occurred at 1 h and plasma geniposide was eliminated nearly completely within 12 h. The AUC_{0→ ∞} values of geniposide were 6.99 ± 1.27 h · µg/ml and 6.76 ± 1.23 h · µg/ml after i.v. administration of 10 mg/kg and p.o. administration of 100 mg/kg of geniposide, respectively. The absolute oral bioavailability (%F) of geniposide was calculated as 9.67%. After p.o. administration of geniposide, the AUC_0→4h values in tissues were in the order of kidney > spleen > liver > heart > lung > brain. This study improved the understanding of the pharmacokinetics, bioavailability and tissue distribution of geniposide in rats and may provide a meaningful basis for clinical application of such a bioactive compound of herbal medicines. Copyright © 2013 John Wiley & Sons, Ltd.     

Pharmacokinetics and absolute bioavailability of ibuprofen after oral administration of ibuprofen lysine in man

The lysine salt of d,l-2-(4-isobutylphenyl)-propionic acid (ibuprofen lysine) was administered as a single oral dose of 500 mg by means of commercially available coated tablets (Imbun).* To assess the absolute bioavailability of ibuprofen after its oral application as a lysine salt, intravenous injections of ibuprofen solutions containing 200 mg and 400 mg of the drug served as reference application. In a partially randomized cross-over design, 8 healthy male volunteers received three different single dose administrations which were separated by wash-out periods of 4 days each. Ibuprofen plasma concentrations were determined by HPLC using direct injection, pre-column enrichment and column switching techniques. From the results of intravenous injections one can deduce linear ibuprofen pharmacokinetics within the considered dosage range, with corresponding AUC0-infinity values of 3786 micrograms * min ml-1 and 7260 micrograms * min ml-1 for the 200 mg and 400 mg doses, respectively. The values of plasma clearances as well as those of different volumes of distribution showed remarkable constancy after evaluation from both intravenous injections. The absorption of orally administered ibuprofen lysine proved to be rapid, resulting in a mean peak plasma level (Cmax) of 31 micrograms ml-1 ibuprofen and in a mean time to peak (tmax) of 45 min. The absolute bioavailability of ibuprofen amounts to 102.7 per cent, indicating a complete absorption of ibuprofen when administered as its lysine salt. Drug tolerability was excellent for the oral administration of ibuprofen lysine as well as for the intravenous treatments with ibuprofen free acid. Only mild and transient adverse drug reactions such as mild burning or dragging sensation during injection or mild redness at the site of injection were reported.     

Pharmacokinetics of temazepam after day-time and night-time oral administration

Summary The pharmacokinetic disposition of temazepam was compared after a day-time and night-time dose in an open randomised crossover study. Twelve healthy male volunteers received a single oral dose of 20 mg temazepam in a soft gelatine capsule at 0900 h or 2200 h. Blood samples were taken immediately before dosing and at selected times over the 36-h period after each dose.The absorption of temazepam was slower after evening administration; the absorption half-life and time to reach maximal plasma concentration being 0.53 h and 1.67 h respectively, compared to 0.38 h and 1.02 h following morning administration. Considering distribution characteristics, evening administration produced a lower peak plasma temazepam concentration (362 ng/ml) compared with a day-time level of 510 ng/ml. Distribution half-life after night-time administration was increased compared with day-time administration (1.76 h vs 1.03 h). A significantly higher percentage of the drug, relative to C_max, remained in the plasma at 8 and 24 h after evening dosing (39.3 and 15.4% compared to 24.7 and 11.2% following day-time administration). In spite of the half-lives of absorption, distribution and elimination all being longer after the evening dose, the overall bioavailability, as measured by the area under the curve (AUC) was comparable after the two times of administration. Similarly the difference in the mean residence time (MRT) of the two doses was within accepted limits.It is concluded that a chronopharmacokinetic effect was seen for temazepam; however it is unlikely to be of any clinical significance.     

Pharmacokinetics and metabolism of isosorbide-dinitrate after intravenous and oral administration

Summary The bioavailabilities of a conventional and two slow release 20 mg isosorbide dinitrate (ISDN) formulations were compared after oral administration in a three way cross-over study in 8 male volunteers. In a further group of 6 male volunteers the pharmacokinetics and metabolism of ISDN were investigated after intravenous infusion of a median dose of 14.1 mg for 2.5 h. A new analytical procedure was developed for the determination of isosorbide-5-mononitrate-2-glucuronide (IS-5-MN-2-Glu) and of isosorbide (IS). Kinetic data analysis on a molar basis was performed by the program package KINPAK providing model independent parameters. The median elimination half-lives of ISDN, IS-5-MN, IS-2-MN and IS-5-MN-2-Glu were 0.7, 5.1, 3.2 and 2.5 h, respectively. The systemic clearance of ISDN was 3.7 l/min and the distribution volume 2521 (3.1 l/kg). Apart from IS-5-MN-2-Glu, with a renal clearance of 5.9 l/min which suggested substantial glucuronidation in the kidney, the renal clearances of ISDN, IS-5-MN, IS-2-MN and the corresponding amounts excreted were negligible. 27.8% of the administered ISDN was excreted as IS-5-MN-2-Glu (8.7%) and IS (19.1%). Calculations based on the two mononitrate metabolites formed from ISDN showed an incomplete recovery of 84.1%, leading to the assumption that a simultaneous denitration to IS must have occurred. The rate of denitration at each nitro group in ISDN was almost twice as high as for the same position in the corresponding mononitrate. The bioavailability of the conventional ISDN formulation was 19%, although complete absorption was indicated by comparison of the percentages of mononitrate metabolites formed after the different routes of administration. On the same basis the absorption of the two sustained release formulations was found to be poor.Preliminary results were presented at the 2nd World Conference on Clinical Pharmacology and Therapeutics, Washington, 1983     

Pharmacokinetics of proxyphylline in adults after intravenous and oral administration

Summary Serum concentrations and urinary excretion of proxyphylline have been measured in five healthy adults after intravenous (29 µmol/kg), single oral (21 µmol/kg) and multiple oral (21 µmol/kg three times a day) doses to produce steady state. The mean peak time after oral administration was 29 min. The mean fraction absorbed was 1.09 calculated from serum concentrations, and 1.05 calculated from urinary excretion of the drug. The apparent volume of distribution was 0.61 l/kg (0.53–0.72 l/kg), 26% higher in males than in females. A two-compartment open model was found to describe the decline in the serum concentrations, giving a mean distribution half-life of 6 min. The intersubject ranges of biological half-life were 8.1–12.1 h and 8.3–12.6 h calculated from serum and urine data, respectively. 24% (18–29%) of the dose was excreted unchanged in urine, which agreed with the relationship between the calculated total body clearance and the renal clearance of the drug.Fellow of the Norwegian Research Council for Science and the Humanities     

Pharmacokinetics of ketorolac tromethamine in humans after intravenous,intramuscular and oral administration

Summary The pharmacokinetics of ketorolac tromethamine, a potent non-narcotic analgesic agent used for relief of moderate to severe pain, has been studied in 15 healthy volunteers who received single 10 mg doses intravenously (i.v.), intramuscularly (i.m.) and orally (p.o.) in a three-way cross-over design.The kinetics of i.v. ketorolac were characterized by a terminal half-life of 5.09 h, a small plasma clearance (CL = 0.35 ml·min^–1·kg^–1) and a small tissue distribution (V_ss=0.111·kg^–1, V=0.17 l·kg^–1; mean (SD). Following i.m. and p.o. administration, peak levels of approximately 0.8 µg/ml were rapidly attained (t_max = 0.8 and 0.9 h, respectively) and the systemic bioavailability was essentially complete.     

Pharmacokinetics of paracetamol (acetaminophen) after intravenous and oral administration

Summary Plasma paracetamol concentrations were measured in 6 volunteers after single intravenous (1000 mg) and oral (500 mg, 1000 mg and 2000 mg) doses of the drug. Paracetamol levels declined multiphasically with a mean clearance after intravenous administration of 352±40 ml/min. A two-compartment open model appeared to describe the decline adequately. Comparison of the areas under the plasma concentration-time curves (AUC) indicated that oral bioavailability increased from 0.63±0.02 after 500 mg, to 0.89±0.04 and 0.87±0.08 after 1000 mg and 2000 mg, respectively. As a consequence of the incomplete bioavailability of paracetamol, as well as its multicompartmental distribution, accurate estimates of its distribution volume and clearance cannot be obtained if the drug is given orally. However, an estimate of its total plasma clearance may be derived from the AUC after a 500 mg oral dose.     

Pharmacokinetics and relative bioavailability of cyclobarbital calcium in man after oral administration

Summary The pharmacokinetics and relative bioavailability of cyclobarbital calcium have been studied after oral administration of Phanodorm, of tablets according to the Formularium Nederlandse Apothekers (1968; FNA), and an aqueous solution. Six healthy volunteers participated in the investigation on three occasions and each received the three preparations. The dose administered was 300 mg cyclobarbital calcium. Plasma concentrations of cyclobarbital were determined at regular intervals. Absorption from the three preparations was rapid and was faster from the solution. Peak concentrations were usually attained within 1 h. The elimination of cyclobarbital could be described by a single first-order process with an average half-life of 11.6 h (range 8 – 17 h). There was little intra-subject variation of the half-life. Relative bioavailability for each volunteer was estimated by comparing the areas under the plasma concentration curves. The FNA-tablets and Phanodorm exhibited similar bioavailability, whereas the average bioavailability of the solution was 78% of that of FNA-tablets; the reason for this unexpected finding is unknown. It was concluded that cyclobarbital cannot be regarded as a uniformly suitable drug for the treatment of insomnia. The long half-life that was apparent in some of the volunteers (15 – 17 h) creates a substantial risk of residual effects on the following morning. In principle, however, the calcium salt of cyclobarbital may be used for induction of sleep, because of its rapid absorption.     

Pharmacokinetics,tissue distribution and bioavailability of nitrendipine solid lipid nanoparticles after intravenous and intraduodenal administration

Purpose: The aim of this research was to study whether the bioavailability of nitrendipine (NDP) could be improved by administering nitrendipine solid lipid nanoparticles (SLN) duodenally to rats.

Methods: Nitrendipine was incorporated into SLN prepared by hot homogenization followed by ultrasonication method. SLN were produced using various triglycerides (trimyristin, tripalmitin and tristearin), soy phosphatidylcholine 95%, poloxamer 188 and charge modifiers (dicetyl phosphate, DCP and stearylamine, SA). Particle size and charge measurements were made with a Malvern Zetasizer. Pharmacokinetics of nitrendipine SLNs (NDP-SLNs) after intravenous (i.v.) and intraduodenal (i.d.) administration to conscious male Wistar rats were studied. Tissue distribution studies of NDP-SLNs were carried out in Swiss albino mice after i.v. administration and compared to nitrendipine suspension (NDP-Susp).

Results: Average size and zeta potential of SLNs of different lipids, with and without charge modifiers ranged from 101.9 ± 3.0 to 123.5 ± 3.0 nm and ? 35.1 ± 0.5 to +34.6 ± 2.3 mV, respectively. AUC_(0–∞) was increased (up to 4.51-folds) and clearance was decreased (up to 4.54-folds) after i.v. administration of NDP-SLNs with and without charge modifiers compared to NDP-Susp. Effective bioavailability of NDP-SLNs were 2.81–5.35-folds greater after i.d. administration in comparison with that of NDP-Susp. In tested organs, the AUC and MRT of NDP-SLNs were higher than those of NDP-Susp especially in brain, heart and reticuloendothelial cells containing organs.

Conclusions: SLN are suitable drug delivery systems for the improvement of bioavailability of nitrendipine. Negatively and positively charged SLN were better taken up by the liver and brain, respectively.     

Pharmacokinetics,tissue distribution and relative bioavailability of geniposide-solid lipid nanoparticles following oral administration

Abstract

Geniposide has various pharmacological effects; however, low oral bioavailability limits its clinical utility. This study explores the pharmacokinetics, tissue distribution and relative bioavailability of geniposide-solid lipid nanoparticles (SLNs) following oral administration. The geniposide solution and geniposide-SLNs were orally administered to the rats, respectively. The C_max value of geniposide in the geniposide-SLNs was significantly higher than that obtained with geniposide solution. Compared with the geniposide solution, the t_1/2 and MRT were prolonged; the CL and V1/F were increased with geniposide-SLNs. The AUC_0–∞values of geniposide-SLNs were 50 times greater than geniposide solution. The ratios of AUC_{0–8 h} in the liver, spleen, heart, kidney, brain and lung of the geniposide-SLNs to geniposide solution were 25.93, 4.28, 27.91, 10.15, 5.16 and 16.22, respectively. Prepared geniposide-SLNs are very helpful for increasing the bioavailability of geniposide. These data suggest that SLNs are a promising delivery system to enhance the oral bioavailability of geniposide.     

An open-label, single-dose bioavailability study of the pharmacokinetics of CAT-354 after subcutaneous and intravenous administration in healthy males

AIM

To assess the bioavailability and pharmacokinetics of CAT-354, an anti-IL-13 human monoclonal IgG4 antibody, following subcutaneous (s.c.) and intravenous (i.v.) administration.

METHODS

This was a single-dose, randomized, open-label, parallel-group bioavailability study. Healthy male subjects aged 20–54 years were randomly assigned to one of three dose groups (n= 10/group) to receive CAT-354: 150 mg i.v.; 150 mg s.c. or 300 mg s.c. (two 150 mg injections). Serum pharmacokinetics, adverse events (AEs), vital signs, electrocardiograms and laboratory parameters were assessed.

RESULTS

CAT-354 showed bioavailability of 62% and 60% after 150 mg and 300 mg s.c. doses, respectively, and linear pharmacokinetics over the dose range tested. Peak serum concentrations in the s.c. groups occurred after 3–9 (median 5) days, with a mean elimination half-life of 19.2 ± 3.1 days (150 mg) and 19.4 ± 3.59 days (300 mg) after s.c. and 21.4 ± 2.46 days after i.v. administration. Volume of distribution at steady state (V_ss) was 4960 ± 1440 ml kg⁻¹ after i.v. (slightly greater than plasma volume). Average apparent clearances (CL/F) were 292 ± 82.3 and 307 ± 109 ml day⁻¹ after 150 and 300 mg s.c., respectively; systemic CL of 188 ± 84.0 ml day⁻¹ after i.v. dosing was consistent with endogenous IgG and reticuloendothelial elimination. No severe or serious AEs occurred. Among 40 reported AEs, 25 were headache, sinus disorders/respiratory symptoms and changes in body temperature perception.

CONCLUSIONS

CAT-354 exhibited bioavailability of approximately 60% when given s.c. to healthy male subjects.     

Pharmacokinetics of xamoterol after intravenous and oral administration to volunteers

Summary The pharmacokinetics of xamoterol, a -adrenoceptor partial agonist under clinical evaluation for the treatment of mild to moderate heart failure, have been studied in 12 healthy male subjects. They received 14 mg i.v. and oral doses of 50 and 200 mg as a tablet and 200 mg as a solution in a 4 way cross-over design.After i.v. dosing the elimination half-life was 7.7 h, the total body clearance was 224 ml·min^–1 and the volume of distribution at steady-state (V_ss) was 48 l. Sixty-two percent of the dose was recovered unchanged in urine. After oral doses, the absolute bioavailability of xamoterol was shown to be 5% irrespective of whether the dose was administered as a tablet or solution. Peak plasma concentrations occurred at about 2 h for the tablet dose and slightly earlier (1.4 h) for the solution. Peak plasma concentration, AUC and urinary recovery of unchanged drug increased in proportion to dose. The apparent elimination half-life after oral doses (16 h) was significantly longer than that observed after an intravenous dose.Despite the low bioavailability, the degree of inter-subject variability of oral bioavailability was small probably indicating that the controlling factor is the hydrophilic nature of the molecule rather than extensive first pass metabolism or poor dissolution of xamoterol from the tablet formulation.     

Area under the curve and bioavailability

The Area Under the Curve (AUC) is proportional to the fraction absorbed only if the clearance is constant and the concentration uniform; in all other cases the bioavailability cannot be determined by comparing AUCs.     

Pharmacokinetics and bioavailability of intravenous,oral, and rectal nitrazepam in humans

The pharmacokinetics and bioavailability of nitrazepam following intravenous, oral (tablet), and rectal (solution) administration were studied in seven healthy, young male volunteers. Nitrazepam plasma concentrations were determined by electron-capture GLC; pharmacokinetic evaluations were made by compartmental analysis (NONLIN) and compared with the results obtained by a less stringent modelling of the data. The plasma concentration-time profile was similar for all three routes of administration. Mean kinetic parameters as obtained by compartmental analysis of i.v. nitrazepam were: distribution half-life 17 min; volume of distribution after equilibrium 2.14 liters/kg; total plasma clearance 61.6 ml/min; elimination half-life 29.0 h. The mean protein unbound fraction of nitrazepam in plasma was 12.3% and the clearance of the unbound fraction was 506 ml/min. Absorption of oral nitrazepam started after the elapse of a lag time (mean value 12 min) and occurred as an apparent first-order process in all but one subject, with a mean absorption half-life of 16 min. Distribution and elimination half-lives were comparable with those following i.v. administration. Following rectal administration of the nitrazepam solution, rapid first-order absorption occurred with a mean lag time of 4 min and a mean absorption half-life of 9 min. Peak times (median 18 min) were significantly shorter than following oral administration (median 38 min), but there was little difference in peak concentrations. The distribution half-life was similar to i.v. and oral administration, but the elimination half-lives were longer with a mean value of 33.1 h. Following i.v. administration a good agreement was found between the results obtained by compartmental analysis using NONLIN and those obtained by a less stringent modelling of the data. Following oral and rectal administration, a good agreement between the two procedures was found for the elimination half-life; estimation of bioavailability, however, was higher by compartmental analysis. The mean bioavailability data showed that absorption is complete when nitrazepam is given orally and almost 20% lower when it is given rectally, but considerable interindividual differences were observed.     

Pharmacokinetics and tissue distribution of chlorpheniramine in rabbits after intravenous administration

Intravenous studies of chlorpheniramine (CPM) were conducted in six New Zealand White male rabbits (mean wt. 3.88 kg). CPM and its two demethylated metabolites in arterial serum and urine were assayed by HPLC. Triexponential equations were needed to fit the i.V. CPM serum data in three rabbits, while biexponential equations were required in the other three rabbits. Harmonic mean of V₁, V_ss, V _area , CL,and terminal t _1/2 were 2.84, 10.8, and 15.5 liters/kg, and 4.14 liters/kg/hr and 2.57 hr, respectively. The average serum protein binding was 44%. The average blood to plasma concentration ratio was 1.85. Estimated mean hepatic blood extraction ratio based on i.v. studies was 0.88. Tissue distribution studies showed rapid and extensive uptake of CPM by various organs such as lung, kidneys, and brain after i.v. bolus injection, as their concentrations were 160-, 80-, and 31- fold higher than the plasma level. The amount of CPM in the muscle was calculated to represent about 50% of CPM present in the body near the steady state. Variation in plasma protein and tissue binding was postulated to be an important factor for the observed marked interspecies difference in the apparent volume of distribution of CPM. Only 2% of the dose was excreted unchanged in the urine.     

Pharmacokinetics and relative bioavailability of heptabarbital and heptabarbital sodium after oral administration to man

Summary A method has been developed for the quantitative determination of heptabarbital [5-(1-cyclohepten-1-yl)-5-ethylbarbituric acid] in human plasma after administration of single therapeutic doses of the drug. It involves a single extraction step followed by gas chromatography with alkali flame ionization detection, and the results were linear in the concentration range 0.125 – 5.0 µg/ml plasma. The pharmacokinetics and relative bioavailability of heptabarbital and heptabarbital sodium were studied in a crossover design in 7 healthy volunteers after oral administration of 20 tablets containing 200 mg heptabarbital and hard gelatine capsules containing an equivalent amount of its sodium salt. Heptabarbital concentrations in plasma were determined at regular intervals. The absorption of heptabarbital from the tablets was quite slow and peak level times varied from 1.5 to 4 h. The sodium salt was absorbed more rapidly and peak concentrations occurred between 1/3 and 2 h. In all cases the elimination of heptabarbital could be described by a single first-order process with an average half-life of 7.6 h (range 6.1 – 11.2 h). The half-life of the drug in each individual was about the same in the two trials. The relative bioavailability in each volunteer was estimated by comparing the areas under the plasma concentration curves. The sodium salt had an average bioavailability of 83% relative to the free acid. In some volunteers urinary excretion of unchanged heptabarbital was measured; cumulative excretion amounted to 0.16 – 0.30% of the administered dose. Four volunteers received one tablet each night for eight or ten days, but no accumulation was found. In three volunteers the half-life of the drug prior to and after these experiments did not change, whereas in the other volunteer the half-life decreased from 7.1 to 4.6 h. The possibility of enzyme induction should be considered when heptabarbital is taken regularly. It was concluded that heptabarbital was a suitable drug for the treatment of insomnia, since its half-life was rather short. Heptabarbital sodium may be used for induction of sleep, whereas Medomin^® tablets, i.e. heptabarbital free acid, may be prescribed when the maintenance of sleep is the primary reason for treatment with a hypnotic drug.     

Pharmacokinetics of ketanserin and its metabolite ketanserin-ol in man after intravenous,intramuscular and oral administration

Summary The pharmacokinetics of ketanserin (R 41468), a novel serotonin S₂-receptor blocking agent widely investigated for its effect on acute and chronic hypertension, has been studied in 10 healthy male subjects. They received single 10 mg doses i.v. and i.m., and 20, 40 and 60 mg solutions of ketanserin by mouth, in a five-way cross-over design. The model-independent kinetics of i.v. ketanserin were characterized by a terminal half-life of 14.3±4.4 h, a moderate plasma clearance (CL=565±57 ml/min) and a large tissue distribution (V_ss=268±71 l, V_z=703±204 l; mean ± SD). Following i.m. administration, peak levels of nearly 200 ng/ml were attained within 10 minutes and the absolute bioavailability was 112±23%. After oral dosing, peak levels of ketanserin were reached within 1 h. The peak level and AUC increased in proportion to the dose. The absolute bioavailability was 46.8, 50.4 and 55.5% for 20, 40 and 60 mg doses and they conformed to the predicted bioavailability based on i.v. clearance data. The terminal half-life of 17 h and the urinary excretion of parent drug (about 0.7% of the dose) were similar after oral and parenteral dosing. The kinetics of ketanserin-ol, the major metabolite of ketanserin formed by ketone reduction, was also studied. Because of its negligible pharmacological activity, the contribution of ketanserin-ol to the overall therapeutic effect of ketanserin is small, in spite of its 1.6-times (parenteral) to 3.2-times (oral) higher plasma level than that of ketanserin. The particular role of the metabolite is discussed in the light of the clinical pharmacokinetics of ketanserin.     

Cocaine pharmacodynamics after intravenous and oral administration in rats: relation to pharmacokinetics

  Rationale: To design optimal dose regimes for oral cocaine, it is essential to characterize pharmacokinetics (PK) of cocaine after IV and PO administration. Objectives: To investigate the absolute bioavailability of oral cocaine, its effectiveness and the relation between PK and PD in a within-subject design. Methods: We used the effects of IV and PO cocaine on a contingency-controlled timing behavior, the differential reinforcement of low rate schedule (DRL 45-s) in 3-h sessions, as the PD measures [i.e., the shorter-response rate (srr) and the reinforcement rate (rr)]. Cocaine PK parameters were determined by simultaneous modeling of the concentration-time profiles (CTPs) after IV 2 mg/kg and PO 20 mg/kg cocaine administration. The absolute oral cocaine bioavailability was determined pharmacokinetically (F) and pharmacodynamically (F_srr and F_rr). Results: IV and PO cocaine increased the shorter response rate and decreased the reinforcement rate in a dose- and time-related fashion, which mirrored the respective prototypical serum cocaine CTPs. After the absorption phase, the serum cocaine CTP of PO cocaine paralleled that of IV cocaine. The duration of action for PO cocaine was longer than that for IV cocaine owing to its larger mean residence time. The active metabolite, norcocaine, was not detected after IV but after PO cocaine administration. The value of F was 4.66% which was significantly lower than the values of F_srr (13.67%) and F_rr (32.63%). Furthermore, the concentration-effect relations for the reinforcement rate revealed that PO cocaine was more potent than IV cocaine. Conclusions: Oral cocaine is more effective behaviorally than from predictions made in terms of its PK. The differences in active metabolite profiles as well as the rate and extent of acute tolerance for IV versus PO cocaine may account for the greater potency observed for oral cocaine. Received: 23 July 1998 / Final version: 2 February 1999     

Absolute bioavailability of chlorthalidone in man: A cross-over study after intravenous and oral administration

Summary Seven normal human volunteers each received a constant-rate infusion of chlorthalidone for 2 h, and the same (commonly 50 mg) single oral dose on separate occasions. The concentration of unchanged chlorthalidone was analyzed over a 100 to 220 h period in plasma, red blood cells, urine and faeces after both dosage forms. A three compartment model was required to describe the intravenous plasma concentrations in five of the subjects. A two compartment model sufficed to account for the decay of the oral plasma concentrations in all seven subjects. The mean plasma t_1/2 after i.v. dosing was 36.5 h (±10.5 SD), and the mean plasma t_1/2 after oral doses was 44.1 h (±9.6 SD). The mean red blood cell concentration t_1/2 after i.v. doses was 46.4 h (±9.9 SD), and the mean red blood cell t_1/2 after the oral doses was 52.7 h (±9.0 SD). The shorter i.v. half-live was not equally manifest in all subjects, being mainly apparent in three of them. In all cases the urinary excretion rate plots were parallel to the plasma concentration curves. As the faster decay after i.v. administration was not accompanied by increased renal clearance, the difference must have been due to non-renal mechanism. The mean total of 65.4 (±8.6 SD) % of the intravenous dose was excreted in urine over infinite time, whereas the mean total excretion after the oral dose was 43.8 (±8.5 SD) %. Faecal excretion ranged from 1.3–8.5% of dose in the i.v. study to 17.5–31.2% of dose in the oral study. The sum of the amounts present in urine plus faeces pointed strongly to an important metabolic route of elimination of chlorthalidone. Bioavailability estimates (F) from three sets of data were — a mean F of 0.61 from plasma concentrations, 0.67 from urinary excretion measurements and 0.72 from the erythrocyte concentrations. Simulations with a non-linear model indicated lesser validity of the estimate from erythrocyte concentrations. It was concluded that the average of plasma and urine data, F=0.64, yielded the best estimate of the oral availability of chlorthalidone 50 mg in man.