Biomedical subjects

J D Pipkin

Publications and source records attributed to J D Pipkin.

7 recordsLinked to original sources

PubMed1993

Enhanced bioavailability of cefoxitin using palmitoylcarnitine. II. Use of directly compressed tablet formulations in the rat and dog.

The performance of tablets containing the absorption enhancer palmitoylcarnitine chloride (PCC) and the antibiotic cefoxitin (CEF) was determined by direct placement of tablets in the rat stomach, small intestine, and colon. While the bioavailability (F) of tablets containing 12 mg CEF without PCC ranged from 0.6 to 3.9%, the addition of 24 mg PCC resulted in an enhanced CEF bioavailability in the rat colon (mean +/- SD: F = 57 +/- 19%) and rat jejunum (F = 71 +/- 16%) but not in the rat stomach. Following oral administration to dogs, tablets of 200 mg CEF without or with 600 mg PCC resulted in the same low bioavailabilities (7.0 +/- 10.3 and 7.0 +/- 3.6%, respectively). However, when these tablets were enteric coated, PCC improved CEF bioavailability from 2.44 +/- 1.84 to 29.0 +/- 13.4%. Therefore, the use of enteric-coated direct compressed tablets containing PCC and direct compression excipients improved the peroral bioavailability of a poorly absorbed compound.

Animals↗

PubMed1993

Evaluation of sustained/controlled-release dosage forms of 3-hydroxy-3-methylglutaryl-coenzyme a (HMG-CoA) reductase inhibitors in dogs and humans.

Seven sustained/controlled-release dosage forms were designed for gastrointestinal delivery of lovastatin or simvastatin, two potent HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia. The in vivo performance of these formulations was evaluated in dogs and healthy volunteers in terms of the cholesterol lowering efficacy and/or systemic concentrations of HMG-CoA reductase inhibitors. Results from the present and previous studies suggest that, through the controlled release of HMG-CoA reductase inhibitors, sustained lower plasma concentrations of HMG-CoA reductase inhibitors may result in an equal or better therapeutic efficacy.

Adult↗

PubMed1988

Application site dependent ocular absorption of timolol.

Ocular absorption of timolol in rabbits was studied after topical ocular administration of 3H-timolol in an eyedrop or in silicone cylindrical devices that released timolol at 7.2 micrograms/h. The devices were applied in either the inferior or superior conjunctival sac. Timolol concentrations were nearly equal in the inferior and superior portions of ocular tissues when the drug was administered in an eyedrop. Administration in the devices resulted in unequal timolol distribution in the cornea, conjunctiva, sclera, and iris-ciliary body. Timolol concentrations were higher in the part of each tissue that was closer to the site of the device application. Unequal concentrations of timolol in the superior and inferior part of the eye and very low timolol concentrations in the aqueous humor indicated that timolol was absorbed mainly via a noncorneal route from the device placed in the inferior conjunctival sac. Induced blinking at one minute intervals did not change ocular absorption of timolol. Compared with inferior conjunctival sac applications, placement of the devices in the superior conjunctival sac resulted in increased corneal and total ocular absorption of timolol as indicated by higher timolol concentrations in the aqueous humor and by a smaller difference between concentrations in the superior and inferior portions of the examined tissues. The application site dependent ocular absorption indicated that controlled release of timolol in the tear fluid did not result in a uniform timolol distribution in the preocular tear fluid of rabbit eyes.

Absorption↗

PubMed1984

Dissolution and ionization of warfarin.

It has been shown in recent studies that warfarin exists in the solid state and in some nonaqueous solvents as a cyclic hemiketal. The present study was undertaken to investigate the ionization and ionization kinetics of warfarin, to confirm the probable existence of the cyclic hemiketal in aqueous solution, and to determine the possible consequences of the cyclic hemiketal to acyclic enol equilibrium and ionization kinetics on the dissolution rate of warfarin. The equilibrium aqueous solubility of un-ionized warfarin acid at 25 degrees C and ionic strength 0.5 (with potassium chloride) was found to be 1.28 X 10(-5) M, and its observed macroscopic pK alpha was 5.03-5.06, depending on the method of determination. By comparing the aqueous pK alpha of warfarin to phenprocoumin, a hydroxycoumarin that cannot exist in the cyclic hemiketal form, the hemiketal-acyclic enol ratio was estimated to be approximately 20:1. By stop-flow spectrophotometry, the ionization rate of warfarin (pH 3.5 jumped to pH 6.5) was found to have t1/2 less than 1-2 X 10(-3) s. The dissolution rate of warfarin from a rotating disk (600 rpm), as a function of pH, was measured under nonbuffered but pH-stat conditions (mu = 0.5 with potassium chloride). The pH-dissolution rate profile for warfarin agreed with that calculated from an equation derived previously to describe the dissolution of instantaneous ionizing acids, i.e., the profile was not perturbed from that expected from an acid of aqueous solubility 1.28 X 10(-5) M (un-ionized form) and pK alpha 5.06.

Chemistry, Pharmaceutical↗

PubMed1982

Thiamine whole blood and urinary pharmacokinetics in rats: urethan-induced dose-dependent pharmacokinetics.

The whole blood pharmacokinetics of thiamine after intravenous administration of thiamine hydrochloride (4, 12, and 36 mg/kg) to rats anesthetized continuously with ether (inhalation) or urethan (1 g/kg ip) were studied. Urinary excretion of thiamine after intravenous administration of thiamine hydrochloride to rats lightly anesthetized with ether was also investigated. At any particular dose, thiamine displayed apparent classical two-compartment model behavior in the time range studied. Under urethan anesthesia, thiamine displayed apparent dose-dependent kinetics as measured by the changes in the pharmacokinetic parameters, AUC,Vd(area), t0.5 beta, and total body clearance, ClTB, with dose. However, when ether anesthesia was used, thiamine displayed dose-independent pharmacokinetic behavior. These results suggest that care should be taken in the interpretation of pharmacokinetic data obtained in anesthetized animals, particularly when urethan anesthesia is used.

Anesthesia↗

PubMed1978

Thiamine whole blood pharmackinetics in rats using both a specific S-thiamine liquid scintillation assay and the thiochrome fluorescence assay.

The study of factors altering the CNS and GI absorption of thiamine in rats required the development of a specific assay for thiamine from 100-microliter samples of blood and plasma and small quantities of tissue. The specific thiochrome fluorescence assay for thiamine was modified to handle microsamples and to use S-thiamine. This sensitive and specific radioassay using S-thiamine gave pharmacokinetic parameters for 4-mg/kg iv doses of thiamine in rats equivalent to those using the less sensitive thiochrome fluorescence assay. The new assay, because of its lower limit of detection, allowed the study of the time profile of thiamine after a 1-mg/kg iv dose in rats. Such a time profile could not have been followed using the standard thiochrome fluorescence assay.

Animals↗

PubMed1976

Phenylbutazone ionization kinetics.

Phenylbutazone has been associated with bioavailability problems and has shown nonclassical behavior in phase-transport studies. This nonclassical behavior has been attributed, in part, to the fact that phenylbutazone, as a carbon acid, undergoes noninstantaneous ionization kinetics. Instantaneous reaction is an assumption made in many diffusion-limited transport models involving a simultaneous ionization reaction. The ionization kinetics of phenylbutazone were determined at an ionic strength of 0.1 and 25 degrees using a stopped-flow spectrophotometer. A log kobs versus pH profile for the approach to the ionization equilibrium was determined, and a mechanism consistent with the profile was postulated. The percent enol versus the diketo form of phenylbutazone acid as well as pKaenol and pKadiketo was kinetically calculated. The protonation reaction was highly catalyzed by general acids while the deprotonation reaction was highly catalyzed by general bases. The general acid, water, was a poor proton donor to the anionic form (the so-called mesomericanion) of phenylbutazone.

Buffers↗