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Biomedical subjects

K K Midha

Publications and source records attributed to K K Midha.

At least 235 records · Page 13Linked to original sources
PubMedDate not supplied

The relative bioavailability of a commercial propranolol hydrochloride tablet in man.

A relative bioavailability study of conventional tablet of propranolol hydrochloride was conducted in a group of 18 healthy volunteers employing the innovator's product as the reference tablet formation. Based on plasma levels of propranolol for the 24 h following administration of 2 x 40 mg oral propranolol hydrochloride tablets, the relative extent of availability was shown to be 100.8 per cent for the test tablet formulation; no significant differences were detected between formulations with respect to any of the pharmacokinetic parameters examined. Large intersubject variations in plasma propranolol concentrations and the subsequently calculated areas under the plasma concentration/time curves were attributed to substantial presystemic biotransformation differences.

Adolescent↗
PubMedDate not supplied

Pharmacokinetics of glucuronidation of propranolol following oral administration in humans.

Pharmacokinetic and bioavailability parameters of propranolol were estimated in 10 healthy adult subjects after single oral doses of two commercial tablet formulations of propranolol hydrochloride (2 X 40 mg). Plasma concentrations of propranolol were determined by a high-performance liquid-chromatographic (HPLC) assay. Peak plasma concentrations of propranolol glucuronide were 6-8 times those of the corresponding peak propranolol plasma concentrations. The mean resident time (MRT) of propranolol and of propranolol glucuronide was determined for each subject for both formulations. The MRT of the parent drug was found to be longer than the MRT of the glucuronide metabolite for each of the subjects examined. Statistical moment analysis indicated that this phenomenon is attributable to extensive presystemic glucuronidation of the parent drug.

Administration, Oral↗
PubMedDate not supplied

A bioequivalency study of two trifluoperazine tablet formulations using RIA and GC-MS.

Two sensitive analytical procedures, a radioimmunoassay (RIA) and a mass fragmentographic (GC-MS) method, were used to quantitate plasma trifluoperazine concentrations over 24 h in five healthy male volunteers following single 5 mg doses of two trifluoperazine tablet formulations (A and B) in a two-way cross-over design. Bioavailability in terms of area under the plasma concentration versus time curve to 24h or extrapolated to infinity, maximum plasma concentration and time to maximum plasma concentration using either RIA or GC-MS was not statistically significantly different from one formulation to the other. Also, there were no statistically significant differences between GC-MS and RIA values for AUC24(0) and Cmax for each of the two formulations examined. However, the mean AUC24(0) RIA/GC-MS ratios for formulations A and B were 3.1 and 3.4, respectively, while the mean Cmax RIA/GC-MS ratios were 1.7 and 2.1, respectively. These differences in AUC and Cmax are probably mainly due to the relative non-specificity of the RIA antiserum. Thus, where GC-MS is preferred for pharmacokinetic studies, both analytical procedures can be used for comparative single-dose bioequivalence studies of trifluoperazine. However, both the methods should be tested in patients in order to establish the suitability of one procedure over the other for the study of plasma level versus clinical response correlations.

Adult↗
PubMedDate not supplied

Analytical methods validation: bioavailability, bioequivalence and pharmacokinetic studies. Conference report.

This is a summary report of the conference on Analytical Methods Validation: Bioavailability, Bioequivalence and Pharmacokinetic Studies. The conference was held from December 3 to 5, 1990 in the Washington, DC area and was sponsored by the American Association of Pharmaceutical Scientists, US Food and Drug Administration, Federation International Pharmaceutique, Health Protection Branch (Canada) and Association of Official Analytical Chemists. The purpose of the report is to represent our assessment of the major agreements and issues discussed at the conference. The report is also intended to provide guiding principles for validation of analytical methods employed in bioavailability, bioequivalence and pharmacokinetic studies in man and animals. The objectives of the conference were: 1. To reach a consensus on what should be required in analytical methods validation and the procedures to establish validation; 2. To determine processes of application of the validation procedures in the bioavailability, bioequivalence and pharmacokinetic studies; 3. To develop a report on analytical methods validation (which may be referred to in developing future formal guidelines). Acceptable standards for documenting and validating analytical methods with regard to processes, parameters or data treatments were discussed because of their importance in assessment of pharmacokinetic, bioavailability and bioequivalence studies. Other topics which were considered essential in the conduct of pharmacokinetic studies or in establishing bioequivalency criteria, including measurement of drug metabolites and stereoselective determinations, were also deliberated.

Biological Availability↗
PubMedDate not supplied

Comparison of a new GLC-AFID method with a GLC-MS selected ion monitoring technique and a radioimmunoassay for the determination of plasma concentrations of imipramine and desipramine.

A gas-liquid chromatographic procedure employing an alkali flame ionization detector (GLC-AFID) for the quantitation of imipramine and its major active metabolite, desipramine, in plasma was developed. This method validated a previously reported radioimmunoassay for imipramine and desipramine. The GLC-AFID method was also compared with a GLC-mass spectrometric procedure which employed selected ion monitoring (GLC/MS-SIM) in which specific ions for imipramine and desipramine were monitored. The two methods using gas chromatographic separation were shown to be suitable for therapeutic monitoring of these drugs in patients. The direct immunoassay, which measures the total imipramine plus desipramine, is very useful when large numbers of samples are to be analysed rapidly and it compares favorably with the other two analytical procedures.

Desipramine↗
PubMedDate not supplied

In vitro evaluation of percutaneous absorption of an acyclovir product using intact and tape-stripped human skin.

PURPOSE: To evaluate the use of a flow-through diffusion cell system to assess the absorption and penetration characteristics of drug (acyclovir) products. METHODS: In vitro studies were performed to assess the absorption/penetration of acyclovir using a flow-through diffusion cell system with human skin sections obtained from 19 healthy women following mammoplasty. The skin sections, 200-400 microm thick, were prepared using a dermatome. Acyclovir ointment (approximately 10 mg) spiked with (3)H-labelled acyclovir was applied onto the stratum corneum/epidermis side. The skin sections were continually perfused on the dermis side with sterilized culture medium, Buffered Hanks' Balanced Salt Solution, saturated with a CO(2)/O(2) (5/95%). RESULTS: After 24 hours, the percentages of acyclovir-derived radioactivity (based on dose applied) in different components were as follows: stratum corneum (SC), 0.20+0.28; viable skin (VS), 0.40+0.38; effluent fluid (EF), 0.25+0.53. A second set of experiments was performed using tape stripped (10X) skin sections. Levels of acyclovir-derived radioactivity were VS, 1.21+1.43 and EF, 2.65+2.61, which were threefold higher (p < 0.05) for VS and elevenfold higher (p < 0.05) for EF compared to the results obtained with the intact skin sections. CONCLUSIONS: The SC is the main barrier layer for the penetration of acyclovir through human skin. The use of the flow-through diffusion cell system provides an appropriate in vitro model to assess the absorption/penetration of acyclovir through human skin layers and therefore can potentially be used for dermal formulation characterization and development.

Acyclovir↗
PubMedDate not supplied

Metabolism of methoxyphenamine in man and in monkey.

Metabolites of methoxyphenamine in the urine of human subjects and monkeys were separated by gas-liquid chromatography and identified by comparison of their chromatographic and mass spectrometric behavior with those of synthetic compounds. Aromatic O-demethylation, aromatic ring hydroxylation (both followed by glucuronide conjugation), and N-demethylation were shown to occur in man as well as in monkey. In man these were the principal metabolites, whereas in the monkey three additional unidentified major metabolites were formed.

Adult↗
PubMedDate not supplied

Identification of 3-O-methyl-alpha-methyldopamine as a urinary metabolite of 3,4-methylenedioxyamphetamine in dog and monkey.

3-O-Methyl-alpha-methyldopamine has been separated by gas-liquid chromatography (GC) as a metabolite of MDA in the urine of dog and monkey. The metabolite was identified as its mono- and di-trifluoroacetyl derivatives by comparison of their GC and GC-mass spectral properties with those of synthetic compounds. The amount of metabolite increased on hydrolyzing the urine from dosed dogs and monkeys with a preparation containing beta-glucuronidase and sulfatase.

3,4-Methylenedioxyamphetamine↗
PubMedDate not supplied

Cis-flupentixol metabolites in rat plasma and bile. The first proof of glutathione conjugation at the exocyclic double bond.

The plasma and biliary metabolites of cis-flupentixol (cis-FPT) were studied after ip administration to rats. Cis-FPT sulfoxide was found to be the major phase-I metabolite in plasma and bile. Five biliary metabolites were isolated by gradient elution HPLC and characterized by various spectroscopic methods: F1, 1'-S-glutathionyl-10,1'-dihydroFPT sulfoxide; F2, cis-FPT sulfoxide sulfate; F3, 8-O-(or 7-O) glucuronyl-cis-FPT; F4, cis-FPT sulfoxide; and F5, cis-FPT glucuronide. A novel non-enzymatic addition of glutathione (GSH) onto the exocyclic double bond was demonstrated to occur for the first time with not only flupentixol and certain of its metabolites, but also with other psychotropic drugs with a tricyclic nucleus and an exocyclic double bond. Specifically, these nonenzymatic additions of GSH were observed with cis-FPT, trans-FPT, cis-FPT sulfoxide, cis-, trans-dealkylFPT, cis-FPT N-oxide, cis-chlorprothixene, cis-thiothixene, and cyclobenzaprine. Among them, cis-FPT sulfoxide showed the most potent adduct formation activity, and the product was characterized to be identical with the in vivo metabolite F1 of cis-FPT.

Animals↗
PubMedDate not supplied

Identification of phase-I and phase-II metabolites of fluphenazine in rat bile. Intact glucuronide and sulfate conjugates.

In rat bile following ip administration of fluphenazine (FLU) dihydrochloride (20 mg/kg body weight), phase-I metabolites 7-hydroxyfluphenazine (7-HOFLU) and FLU sulfoxide (FLUSO), together with unmetabolized FLU, were isolated and identified by HPLC and fast atom bombardment spectrometry (FAB/MS) and also by comparison with authentic compounds. Two intact glucuronide conjugates of FLU were isolated and identified as phase-II metabolites: 7-hydroxyfluphenazine ring glucuronide (glucuronic acid linked to the aromatic hydroxyl group of 7-hydroxyfluphenazine), and FLU glucuronide (glucuronide linked to the aliphatic group of the side chain of FLU) by HPLC and FAB/MS in comparison with authentic compounds. Further confirmed by FAB/MS were several sulfate conjugates of FLU that were isolated and identified indirectly as phase-II sulfate metabolites: FLU sulfate, 7-hydroxyfluphenazine sulfate and/or 7-hydroxyfluphenazine ring sulfate, and FLU sulfoxide sulfate by HPLC and FAB/MS; their aglycones were identified after sulfatase hydrolysis as FLU, 7-HOFLU and FLUSO. A further phase-II metabolite, for which no authentic standard was available, was tentatively identified as a monoglucuronide of dihydroxy derivative of FLU. To our knowledge, this report provides the first direct evidence of the presence of intact phase-II metabolites of FLU in rat bile.

Animals↗