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The pharmacokinetics and bioavailability of nitroglycerin (GTN) and its metabolites, 1,2-glyceryl dinitrate (1,2-GDN) and 1,3-glyceryl dinitrate (1,3-GDN), were compared after a single 14-hour application of Transderm-Nitro (Ciba-Geigy, Summit, NJ), Nitrodisc (GD Searle, Chicago, IL), and Nitro-Dur II (Key Pharmaceuticals, Kenilworth, NJ) systems to 18 healthy male subjects on 3 separate occasions. A 14-hour intravenous infusion of 15N-labeled GTN was given simultaneously to correct for changes in systemic clearance during the application of each system. Plasma concentrations of 15N-labeled GTN, unlabeled GTN, and their corresponding dinitrate metabolites were measured using a gas chromatography/mass spectrometry method. Results showed that the plasma concentration profiles of nitroglycerin and its metabolites for the three systems were similar during and after system removal. Mean (SD) total amounts (AUCp x CLiv) of GTN transdermally available after adjustment for 15N-labeled GTN clearance were 5.3 (2.1), 5.3 (2.0), and 5.4 (2.6) mg for Transderm-Nitro, Nitrodisc, and Nitro-Dur II, respectively. Mean (SD) AUC values for 1,2-GDN were 44.6 (15.8), 44.3 (16.1), and 42.8 (19.3) ng.h/mL for the 3 systems. Corresponding AUC values for 1,3-GDN were 9.3 (2.9), 9.7 (2.9), and 8.7 (3.0) ng.h/mL. Statistical analysis of the log-transformed data based on 90% conventional confidence interval showed that all 3 systems delivered equivalent amounts of nitroglycerin into the systemic circulation. The AUC ratios for 1,3-GDN to GTN, but not 1,2-GDN to GTN, were statistically different for the intravenous and transdermal routes during all 3 system applications, indicating that the formation and metabolism of 1,3-GDN was dependent on route of administration.

Purpose. The purpose of this study was to use a replicate designed trial to assess the overall, intra- and inter-subject variabilities in pharmacokinetic parameters of CGP 33101 after oral administration of tablets relative to that of powder suspended in water, and to determine the relative proportion of the intra-subject variance to the overall variability.

The effect of the rate of infusion of disodium aminohydroxypropylidene bisphosphonate (APD; CGP 23339A), an inhibitor of bone resorption, on urinary excretion of this agent was studied in a randomized open-label study in 20 cancer patients. Ten patients received 60 mg of APD over 4 h, and the remaining 10 patients received the same dose over 24 h. Urine collected during specified intervals for 72 h after the start of the infusion was analyzed by high-performance liquid chromatography for unchanged APD. Mild and transient adverse experiences were observed in 12 (60%) patients; the most common were headache, fever, and phlebitis at the infusion site. No clinically significant laboratory abnormalities were observed, and none of the experiences were serious enough to require discontinuation of treatment. Cumulative urinary excretion of APD was a linear function of time, increasing rapidly after both the 4- and 24-h Infusions were started. The mean (± standard deviation) cumulative urinary excretion of APD was 51.1 ± 13.0% of the dose in the 20 patients, 55.0 ± 15.0% in the 10 patients given the 4-h infusion, and 47.2 ± 9.9% in the 10 patients receiving the 24-h infusion. Thus, the rate of infusion of the 60-mg dose did not influence retention of APD at 72 h after the start of therapy. Similarly, the presence or absence of bone metastases did not influence cumulative urinary excretion or the retention of APD.

Pentopril (CGS 13945) was administered in 125-mg capsules to eight healthy men on two occasions according to a randomized schedule; on one occasion in the fasting state and on the other occasion immediately following the ingestion of a standardized meal. Unlike captopril, a prototype angiotensin-converting-enzyme inhibitor, there was no significant difference in the peak plasma concentration for either the drug or its active metabolite (CGS 13934) between the fasting and the fed states. There was also no appreciable change in the area under the plasma curve for the drug and its metabolite after administration of drug in the presence of food compared with a fasting state. There was, however, a lag time in drug absorption after ingestion of food, which resulted in a significant increase in peak time for the active metabolite in plasma. Food delays the body's absorption of the drug and hence the appearance of its active metabolite in plasma without any significant effect on the relative bioavailability. Because relative bioavailability is not affected in the presence of food, such a delay may not have any therapeutic importance on chronic administration.

Single-dose and steady-state studies were carried out on separate occasions to examine the bioequivalence of the newly formulated carbamazepine chewable tablet. In the single-dose study, the plasma levels resulting from 2 × 200-mg conventional tablets (CT), 4 × 100-mg chewable tablets swallowed whole (SW), and 4 × 100-mg chewable tablets chewed before swallowing (CHEW) were compared. A randomized 3 × 3 Latin-square design balanced for residual effects, with a 3-week washout period, was used (n = 6). Plasma samples were analyzed by a specific GC method for carbamazepine. The following parameters were used for evaluation: AUC, Cmax, tmax, and t1/2. None of the parameters were significantly different except Cmax and t1/2 values for CHEW and CT. The Cmax was 25% higher and t1/2 was 11% shorter for CHEW than CT. The impact of differences in the peak plasma levels at steady state were examined by pharmacokinetic projection (400 mg b.i.d.) based on the single-dose data and with simulated induction equal to a 50% reduction in t1/2. The projected steady-state CT and CHEW plasma concentrations were similar, with a difference of only 4%. The results demonstrate the bioequivalence of the dosage forms with respect to the extent of absorption, and similar steady-state concentrations of carbamazepine in plasma can be expected. To test the conclusion from the projected study, a separate bioequivalence study to compare CHEW relative to CT was performed at steady state in normal volunteers (200 mg b.i.d.). A randomized 2 × 2 crossover design was used, with each formulation being administered for 24 d followed by a 5-d sample collection period (n = 9). The plasma samples were analyzed by a specific HPLC assay for carbamazepine (CBZ) and the epoxide metabolite (CBZE). Predose levels (days 22–24) were not significantly different for either formulation. In addition, no period effect was observed on the t1/2 of CBZ or on the metabolite fraction, indicating that induction was in a stable state and that steady state for CBZ plasma levels was reached. Again, the results demonstrate that both formulations delivered equal amounts of CBZ to the systemic circulation. The averageCmax of CBZ for CHEW was 7% higher (6.4 versus 6.0 μg/mL) and the median tmax was slightly shorter (2.0 versus 3.0 h) than that for CT, but the differences were not significant. The results are in close agreement with those estimated in the projected study.

A gas chromatographic method for the analysis of ritalinic acid, the major metabolite of methylphenidate, in urine has been developed. Solid phase extraction is employed to afford high recovery of ritalinic acid. The method has a lower limit for reliable quantitation of 1 μ/ml. The reliability and sensitivity of this method make it suitable for human studies.

Pentopril (CGS 13945) was administered in 125-mg capsules to eight healthy men on two occasions according to a randomized schedule; on one occasion in the fasting state and on the other occasion immediately following the ingestion of a standardized meal. Unlike captopril, a prototype angiotensin-converting-enzyme inhibitor, there was no significant difference in the peak plasma concentration for either the drug or its active metabolite (CGS 13934) between the fasting and the fed states. There was also no appreciable change in the area under the plasma curve for the drug and its metabolite after administration of drug in the presence of food compared with a fasting state. There was, however, a lag time in drug absorption after ingestion of food, which resulted in a significant increase in peak time for the active metabolite in plasma. Food delays the body's absorption of the drug and hence the appearance of its active metabolite in plasma without any significant effect on the relative bioavailability. Because relative bioavailability is not affected in the presence of food, such a delay may not have any therapeutic importance on chronic administration.

A method for determining plasma hydrochlorothiazide levels was developed with a sensitivity of 5 ng/ml. Accuracy and precision were demonstrated over the 5–648-ng/ml range by an overall recovery of 95 ± 8%. The detector response was linear for the 5–250-ng/ml range. The method was sufficiently sensitive for hydrochlorothiazide bioavailability studies and also was applicable for the determination of whole blood drug levels. Plasma levels in two subjects reached peak levels of 428 and 450 ng/ml at 2.5 and 2 hr, respectively, after a 50-mg dose. Whole blood levels at 3 hr after the same dose were 547 and 851 ng/ml and were approximately 2.5 times the 3-hr plasma levels.

A method devised for the purification of the microgram amounts of coenzyme Q10 in human blood consists of saponification, solvent extraction, and thin-layer chromatography on silica gel. The concentrate from this chromatography was used in a reaction with ethyl cyanoacetate that gives a blue color caused by ions generated in the reaction. Both of the methoxy groups of coenzyme Q10 are presumably reactive with the reagent, to give a mixture of two products, with one methoxy group replaced by a moiety of ethyl cyanoacetate. This colorimetric reaction is highly specific, and there is no interference from the tocopherols or members of the vitamin K group. The order of magnitude of coenzyme Q10 in human blood is about 1 μg/ml as based on the analysis of the bloods from 18 male and 12 female individuals. The range for the 30 individuals was from 0.4 to 1.8 μg/ml. Although these individuals would generally be considered “normal,” it is not known whether everyone was normal as far as the metabolism of coenzyme Q10 is concerned. The developing knowledge of human blood levels of coenzyme Q10 and the significance of the presence of this substance in the blood would seem to be of considerable importance in relating coenzyme Q10 to health and disease.

Publisher Summary This chapter discusses the assay method of coenzyme Q 10 in blood. This assay is based on the reaction between ethyl cyanoacetate and coenzyme Q 10 (CoQ 10 ) in a basic medium, and the determination of the ions that form and provide the blue color. The residue containing the coenzyme Q 10 that was extracted from the blood sample is purified by thin-layer chromatography on a 1-mm thick silica gel G plate. The sample is applied to the plate in acetone solution as a streak, and the plate is then developed in a 40:60 ether- n -hexane mixture along with a reference spot of pure CoQ 10 .The ether- n -hexane system for thin-layer chromatography can be replaced by a 1:1 chloroform-benzene system. The area opposite the reference spot is scraped and eluted with 15–20 ml of anhydrous ether. The solvent is evaporated from the eluate under a stream of nitrogen, and the colorimetric determination is performed on the dry residue.