Keith K. H. Chan

Stable isotope method for studying transdermal drug absorption: The nicotine patch

A stable isotope‐labeled drug method was used to determine the absolute bioavailability and absorption kinetics of a transdermal nicotine‐delivery system (TTS). TTSs are being developed as an adjunct to smoking‐cessation therapy. Deuterium‐labeled nicotine was infused for 24 hours simultaneously to TTS application in cigarette‐abstinent smokers. In 11 subjects with good patch adhesion, an average systemic dose of 19 mg nicotine was delivered, with average absolute bioavailability of 82%. The rate of nicotine absorption was maximal between 6 and 12 hours after TTS application and declined thereafter, plateauing between 16 and 24 hours at 62% of the maximal rate. Ten percent of nicotine was absorbed after the TTS was removed, demonstrating a reservoir for nicotine in the skin. Our study demonstrates the applicability of stable isotope methods in understanding the clinical pharmacology of transdermal drugs.

Gastrointestinal transit of a solid indigestible capsule as measured by radiotelemetry and dual gamma scintigraphy

The objectives of the present study were to evaluate gastric and small bowel transit times of an indigestible solid matrix and to characterize the specific changes in intraluminal pH as a function of transit time through the gastrointestinal tract. Particular attention was paid to the lag time at the ileocecal junction. A Heidelberg capsule (HC), labeled with 10 µCi Indium-111, was given orally to six healthy male subjects 15 min after oral ingestion of 100 µCi of 99mTc-sulfur colloid as a liquid fatty meal (4 ml/kg). Intraluminal pH was monitored continuously via the HC. Gastric and small bowel transit of the radionuclides was monitored via external scintigraphy at 0.5-hr intervals. Gastric residence times (GRT) of the HC ranged from 2.8 to 4.8 hr, with a mean (±SD) of 3.6 ± 0.8 hr. These values were independent of the individuals weight, height, or body surface area. Small bowel transit times of the HC ranged from 2.8 to >5.5 hr, which were consistent with the reported values of 3 to 5 hr. The lag times of the HC at ileocecal junction ranged from 0.8 to >2.5 hr. The presence of the lag times at the ileocecal junction in all subjects confirmed that it acts as a valve or sphincter. Mouth-to-cecum transit times of the HC occurred within 9.0 hr in 50% of the subjects. In general, following a sharp rise upon pyloric passage of HC the pH dropped slightly but then increased linearly throughout the small intestine. The mean duodenal pH was 5.8 ± 0.8 and the pH at the ileocecal junction ranged from 6.5 to 8.5, with a mean of 7.3 ± 0.7. Passage through the ileocecal junction was associated with a 0.5- to 1.0-unit rise in pH in three subjects who exhibited passage of the HC into the large bowel within the study period. The present data may have implications in the designing of more effective dosage forms with specific delivery to proximal or distal small bowel regions.

A Rapid and Sensitive Method for The Determination of Diclofenac Sodium in Plasma By High-Performance Liquid Chromatography

Abstract A rapid and sensitive high-performance liquid chromatographic method for the determination of diclofenac sodium in plasma has been developed. The method is specific and free of interference from metabolites and common anti-inflammatory agents. The UV detector (215 nm) response was linear over a range of 5-1000 ng/ml. Day-to-day and within-day calibration curves were reproducible. The method was validated by analysis of spiked human plasma samples, partly in a blind fashion. The accuracy and precision of the method are satisfactory over the range of 5-1000 ng/ml. The method was cross-checked with the GC method. Results show a correlation coefficient of 0.983 and a slope of 1.04. The method is suitable for the routine analysis of large numbers of plasma samples usually obtained in bioavailability and pharmacokinetic studies.

Analysis of diclofenac and four of its metabolites in human urine by HPLC.

An HPLC method for the determination of diclofenac (DCF) and four of its metabolites (3′-hydroxydiclofenac, 4′-hydroxydiclofenac, 5-hydroxydiclofenac, and 3′-hydroxy-4′-methoxydiclofenac) in human urine is described. Following base hydrolysis, the samples were neutralized and extracted. Evaporated extracts were reconstituted in mobile phase containing ascorbic acid, and chromatographed, using flow-rate programming, on a reversed-phase column. Absolute recovery (average), was at least 78% for diclofenac and ranged from 75 to 85% for the four metabolites. Standard curves showed linearity over the range of concentrations of 0.2 to 40 ug/mL, using 0.25 mL of urine. Specificity was demonstrated by examining chromatograms of extracts of blank urine from 8 volunteers and 24 study subjects. Good accuracy was observed for all compounds over the concentration range of 0.2 to 40 ug/mL using 0.25 mL of urine. Based on accuracy and precision criteria, the limit of quantitation for all 5 analytes was 0.4 ug/mL, using 0.25 mL of urine. Analysis of urine from subjects with normal and reduced renal function who received diclofenac orally demonstrated that total diclofenac and metabolites excreted in the urine represented approximately 31% and 4% of an oral dose of diclofenac, respectively.

Estimation of statistical moments and steady-state volume of distribution for a drug given by intravenous infusion

Although it is generally recognized that estimates of the area under the drug concentration vs. time curve (AUC)after a dose is rather insensitive to curve-fitting procedures, little is known about estimates of mean residence time (MRT)or volume of distribution at steady-state (Vss),both of which can be derived from area estimates. This question is of particular concern when a drug is given as a short-term constant rate i.v. infusion since the infusion phase is often ignored and blood sampling restricted to the postinfusion period. Two nonexperimental methods for approximating concentration data during infusion termed the linear approximation methodand the imaginary bolus methodwere found to be useful under certain conditions. Both methods provide reasonable estimates of AUCand the area under the first moment of the drug concentration-time curve (AUMC)for drugs with a wide range of pharmacokinetic characteristics. The imaginary bolus method was found to be the better of the two for estimation of MRTand to be widely applicable for this purpose. Vssproved to be highly sensitive to the approximation methods;although the imaginary bolus method is superior to the linear approximation method for estimating Vss,it does not work particularly well for drugs with pronounced multicompartment characteristics. In general, accurate estimation of Vssof drugs given by short-term i.v. infusion requires that at least one drug concentration be determined during infusion.

Expanded version of PKSIM for pharmacokinetic simulations of both metabolite and parent drugs.

We recently described a computer software package for pharmacokinetic simulations called PKSIM. The programs are useful for studying drugs that display either a one-, two-, or three-compartment body model with linear or nonlinear elimination following single or multiple dosing. The practicality of PKSIM owes to its user-friendliness and flexibility to study the impact of pharmacokinetic perturbations and dosage regimens on the drugs concentration-time profile on a real-time basis. The interactive nature of PKSIM allows the test variables to be easily changed after each simulation. High-resolution graphic capabilities also permit presentation of pharmacokinetic profile in various body compartments, either individually or collectively on a single graph. The capability of PKSIM was recently extended to include simulations of both parent drug and metabolite, which adds to the value of the package. The present paper describes in detail the functions of these new features and how they can be applied to better comprehend the pharmacokinetic interdependency between the parent drug and metabolite. In addition to the dose, dosing regimen and rate of drug absorption, influences on the kinetic profiles of parent drug and metabolite by other variables such as formation rate of the metabolite, tissue distribution, tissue redistribution, elimination rates and distribution volume of both entities can be studied with minimal efforts. These new features can be particularly helpful for researchers to study prodrugs and drugs that produce active or toxic metabolites, or better understand the basic concepts of metabolite kinetics.

Pharmacokinetics and Metabolism of Diclofenac Sodium in Yucatan Miniature Pigs

The pig has been suggested as an animal model in biomedical research because of its physiological similarity to man. Therefore, the pharmacokinetics and metabolism of diclofenac sodium (Voltaren) were studied in four Yucatan minipigs after intravenous administration of 25 and 50 mg and oral administration of 50 mg in a solution of 50 mL buffer, 50 mL water, and 200 mL water, and the results compared to historical data in man. The absolute bioavailability after oral administration of 50 mL buffer, 50 mL water, and 200 mL water solutions were 107, 97, and 109%, respectively, compared to approximately 50% in man. The total plasma clearance in minipigs was fivefold slower than in humans (57 ± 17 vs 252 ± 54 mL/hr/kg). The plasma levels of the metabolites 4′-hydroxy, 5-hydroxy, 3′-hydroxy, 4′,5-dihydroxy, and 3′-hydroxy-4′-methoxy diclofenac were considerably lower in minipigs than in man after both iv and oral administration. These results suggest slower metabolism and/or enterohepatic recirculation of the parent drug in minipigs. The volume of distribution of the central compartment was 40% less in humans than in pigs (39 vs 67 mL/kg). The terminal half-lives of the parent drug were similar in pigs (2.4 hr) and humans (1.8 hr). The rate of oral drug absorption increased in the order of 50 mL aqueous, 200 mL aqueous, and 50 mL buffered solutions (Ka = 0.52±0.11, 0.59±0.13, and 1.2±0.7 hr−1, respectively). These trends are similar in man and suggest that both buffering and intake volume can affect diclofenac absorption. Possible reasons for these results include the pH-dependent solubility of this drug and the effect of volume on gastric emptying.

Application of Radiotelemetric Technique in Evaluating Diclofenac Sodium Absorption After Oral Administration of Various Dosage Forms in Healthy Volunteers

A radiotelemetric technique with the Heidelberg capsule (HC) was used to improve the quality of data generated in a bioavailability study involving an enteric-coated (EC) formulation. Further, changes in plasma levels of the drug from other dosage forms were related to changes in the pH environment as determined by the HC. Eight healthy male subjects received the following treatments, 15 min after a light breakfast, according to a randomized, four-way crossover design: (A) HC and 75 mg of a diclofenac sodium aqueous buffered solution; (B) HC and one 75-mg Voltaren EC tablet; (C) HC and one 100-mg Voltaren slow-release (SR) tablet; and (D) HC alone. Each treatment was separated by a 1-week washout period. Two additional subjects subsequently received Treatment B only. Multiple peaks were observed in the drug plasma level–time profiles for the buffered aqueous solution which, in all cases, occurred before gastric emptying of the HC. The multiple peaks were not observed for the Voltaren SR tablet, but a variable absorption lag time occurred which coincided with the gastric residence time of the SR tablet. For the EC tablet the variability of individual plasma level–time profiles was drastically reduced when the time after dosing was adjusted to coincide with gastric emptying of the HC. Finally, the lag time between gastric emptying of the EC tablet and the onset of drug absorption was consistently at 1 hr for all subjects. This lag time was longer than the in vitro disintegration or dissolution times measured under USP conditions.

Pharmacokinetics of ara-C and ara-U in plasma and CSF after high-dose administration of cytosine arabinoside*

SummaryCytosine arabinoside (ara-C) and uracil arabinoside (ara-U) levels were measured in the plasma, cerebrospinal fluid (CSF), and urine of 10 patients exhibiting primary central nervous system lymphoma who received 31 infusions of high-dose ara-C (3 g/m2) as part of their treatment regimen. Peak plasma and CSF ara-C levels were 10.8 and 1.5 μg/ml, respectively. Ara-C was cleared more rapidly from plasma than from CSF. Ara-U appeared rapidly in both plasma and CSF, reaching a peak that was 10 times higher than the corresponding ara-C concentration (104 and 11.2 μg/ml, respectively). Only 4%–6% of the dose was excreted unchanged in the urine, but 63%–73% of it appeared as ara-U within the first 24 h. The presence of leptomeningeal lymphoma did not affect the CSF level of ara-C or ara-U.

Pharmacokinetics of Multiple Daily Transdermal Doses of Nicotine in Healthy Smokers

The plasma concentration–time profiles and pharmacokinetics were characterized for nicotine and its major metabolite, cotinine, after multiple daily application of a nicotine user-activated transdermal therapeutic system (UATTS) to nine healthy smokers. The volunteers abstained from smoking 24 hr prior to and during the course of the study. A 10-cm2 system (designed to deliver 75 µg/cm2/hr) was applied every 24 hr for 5 days, with serial blood samples taken on Days 1 and 5 and after system removal on Day 5. Generally, the nicotine UATTS was well tolerated. Predose nicotine concentrations on Days 3 to 5 indicated that steady state was reached by Day 3. The nicotine pharmacokinetic parameters for Day 1 and Day 5 were similar: the mean (SD) AUC(0-24) values for Days 1 and 5 were 271.7 (50.7) and 311.7 (55.0) ng · hr/ml, the mean (SD) Cmax values were 16.3 (2.6) and 16.8 (2.9) ng/ml, and the median (range) Tmax values on Days 1 and 5 were 12 (9–24) hr and 12 (0–24) hr, respectively. There was only slight or no accumulation of nicotine after multiple dosing as indicated by the Day 5 to Day 1 AUC and Cmax ratios of 1.15 (0.09) and 0.98 (0.06), respectively. Overall, the UATTS system maintained relatively constant plasma nicotine concentrations and is suitable for once-daily application.