Absorption of flurbiprofen in the fed and fasted states.

The oral absorption of flurbiprofen, an antiinflammatory nonsteroidal compound, was compared in the fasted vs the fed state. When ingested as an aqueous solution of the sodium salt, absorption kinetics followed a monoexponential pattern in half of the subjects and a bimodal pattern with a lag time before the onset of the second phase of absorption in the other half of the subjects. When ingested in the free acid form as a tablet either with water (fasted state) or with water 15 min after 330 ml of apple juice (fed state), flurbiprofen absorption was always bimodal, and the lag time before the onset of the second phase was shown to be dependent on the gastric emptying time (r = 0.623, P less than 0.01). The gastric emptying times were significantly longer when the drug was administered in the fed state (average GET = 57 min in the fasted state and 102 min in the fed state; P less than 0.01). These results suggest that gastric emptying effects are one important way in which absorption of drugs can be affected by meal intake.

Gastrointestinal transit of nondisintegrating, nonerodible oral dosage forms in pigs.

Gastrointestinal (GI) transit data necessary as "baseline" or "control" information were collected using pigs as animal models preliminary to bioavailability studies of new sustained action formulations. Density and size effects of nondisintegrating dosage forms on GI transit were investigated. Initially, enteric-coated nondisintegrating magnesium hydroxide caplets (density, 1.5 g/ml; size, 19.6 x 9.5 mm; weight, 1.2 g) were utilized in seven pigs. Prolonged gastric residence (greater than 5 days) occurred in every case for this dosage form. Therefore, nondisintegrating caplets of three densities (1.25, 1.45, and 2.3 g/ml) and three different sizes (large, 20 x 10 mm; medium, 10 x 10 mm; small, 5 x 10 mm) were studied in two more pigs. Roentgenography was used to visualize passage of caplets through the GI tract. Heidelberg pH capsules (size, 8 x 20 mm; density, 1.61 g/ml) were also used in this study. Total GI transit times range from 2 to 33 days for 22 administrations of these nondisintegrating dosage forms. Pigs are found to not be an appropriate model for evaluating bioavailability of nondisintegrating controlled-release dosage forms because total GI transit time (especially gastric transit) is much too long.

Treatment-resistant alopecia areata. Response to combination therapy with minoxidil plus anthralin.

Combination therapy with 5% minoxidil plus 0.5% anthralin was used to treat 51 patients with severe treatment-resistant alopecia areata. History of a cosmetically inadequate response to one or both drugs used as a single agent was present in 50 of the 51 patients. Therapy was relatively well tolerated except by 1 patient who developed a severe irritant reaction and was dropped from the study. Mild to moderate irritant dermatitis was seen in all remaining patients. Cosmetic response was seen in 5 (11%) of 45 patients who completed the 6-month study. Cosmetic response was maintained in 4 (80%) of 5 patients who continued treatment for as long as 84 weeks. All responders had evidence of hair regrowth by week 12. The rapidity and extent of hair regrowth were greater with combination therapy than with either drug used as a single agent. Serum and 24-hour urinary minoxidil determinations showed enhanced systemic minoxidil absorption, which was probably secondary to the irritant dermatitis in some patients; however, no clinical evidence of a systemic minoxidil effect was found. These data suggest that combination therapy using drugs with probable different mechanisms of action may provide a synergistic effect in alopecia areata.

Relationship between contact time of applied dose and percutaneous absorption of minoxidil from a topical solution.

Twenty-two healthy male volunteers completed a four-way, multiple-dose, randomized crossover study to determine the relationship between contact time of applied drug on the scalp and minoxidil absorption from a 2% topical solution. One milliliter of solution was applied twice daily over 150 cm2 of bald scalp to each subject for 6 days. Unabsorbed drug was washed off the scalp after 1, 2, 4, and 11.5 h of contact time in each of four treatments. Cumulative urinary excretion profiles within steady-state, 12-h dosing intervals were well described by straight lines for all treatments, indicating that systemic minoxidil elimination was rate controlled by constant, zero-order percutaneous drug absorption. The extent of minoxidil absorption, expressed as steady-state urinary excretion of unchanged minoxidil, minoxidil glucuronide, or the sum of these, increased in a disproportionate manner with increase in contact time of drug on the scalp. Relative to the amount absorbed after a contact time of 11.5 h, absorption was approximately 50% complete by 1 h and greater than 75% complete by 4 h. This suggests that minoxidil absorption from the vehicle into skin occurs rapidly relative to diffusion through skin. The rate of minoxidil absorption from vehicle into skin was characterized as nonlinear, whereas minoxidil excretion into urine was rate controlled by diffusion from one or more components of the skin which apparently serve as a reservoir, or depot, for minoxidil.

Influence of tretinoin on the percutaneous absorption of minoxidil from an aqueous topical solution.

Nineteen healthy male volunteers completed a three-way, randomized, crossover study to determine the effect of the synthetic retinoid, tretinoin, on percutaneous absorption of minoxidil. Subjects received, for 20 days, twice-daily administrations of 1 ml of an aqueous 2% topical minoxidil solution either alone, with once-daily applications of a 0.05% tretinoin cream, or with once-daily applications of a vehicle control cream. When minoxidil was coadministered with tretinoin cream, minoxidil absorption was increased nearly threefold, compared with a 1.3-fold increase in absorption observed with coadministration of vehicle control cream. Transepidermal water loss measurements, which are sensitive to changes in stratum corneum function, were also significantly increased with tretinoin. No treatment-related changes in stratum corneum thickness were observed on the basis of skin biopsy analysis. The findings indicate that percutaneous minoxidil absorption is enhanced by tretinoin as a result of increased stratum corneum permeability.

Pharmacokinetics of flurbiprofen in man. II. Plasma protein binding.

The plasma protein binding of flurbiprofen was studied using equilibrium dialysis. Dialysis was carried out using plasma samples obtained from five of 15 subjects participating in a crossover bioavailability study. During the course of this study subjects received doses of 100, 200, and 300 mg of flurbiprofen as tablets, and 100 mg as an aqueous solution. Seven samples from each of the four treatments (28 samples/subject) were utilized. An additional 14 samples (seven concentrations prepared in duplicate were prepared using blank plasma obtained from each subject. Concentrations of bound (Cbd) and free (Cfd) flurbiprofen were determined at dialysis equilibrium using a radiotracer technique. Binding curves were constructed for each subject using data obtained from these 42 (28 ex vivo and 14 in vitro) samples. The data was well fitted to a modified Scatchard equation with the addition of a linear term. Although the plasma protein binding of flurbiprofen was nonlinear, within the range of concentrations encountered in the clinical setting, it is minimally so. The Cb/Cf ratio averaged 1524, indicating that in plasma, flurbiprofen is greater than 99.9% bound. The results support the observation that for doses of flurbiprofen usually encountered clinically, the drug obeys linear kinetics.

Absorption of minoxidil after topical application: effect of frequency and site of application.

The effect of application site and frequency on the systemic absorption of topical minoxidil was studied in 52 normal men. Subjects received 1 ml 3% minoxidil solution applied four, six, or eight times daily to the scalp or two, four, six, or eight times daily to the chest for 14 days. Serum and urine were collected and analyzed for minoxidil. No systemic minoxidil accumulation occurred from increasing application frequency to the scalp. Trends in the chest data suggest that absorption may have been lower with the twice-daily regimen. Absorption through the scalp and chest were similar for the lower-frequency regimens; however, trends in the eight-times-a-day regimens suggest that absorption may have been somewhat greater from application to the scalp. Systemic minoxidil accumulation resulting from frequent application is unlikely. The initial dose probably saturates the skin for a period of time longer than the dosing intervals examined.

Elevation of gastric pH with ranitidine does not affect the release characteristics of sustained release ibuprofen tablets.

The effect of elevating gastric pH on the release characteristics of a single unit sustained release (SR) ibuprofen tablet (MOTRIN-SR, Upjohn) was evaluated in 12 young, healthy men. Using a randomized crossover-type design, each subject received three treatments--ibuprofen SR 800 mg, ranitidine 300 mg followed by ibuprofen SR 800 mg, and conventional ibuprofen tablets (2 x 400 mg). Gastric pH, which was monitored radiotelemetrically, was maintained above pH 6 for at least 4 h after pretreatment with ranitidine. In absence of ranitidine, the pH remained mostly below pH 3. Serum levels of ibuprofen were measured for 24 h and urine was collected for 48 h after each treatment. Similarity of the serum levels after the two treatments with ibuprofen SR 800 mg indicated that the release of ibuprofen was unaffected by elevation in gastric pH. Comparison of profiles with the immediate release dosage form indicated that dose dumping did not occur in any subject.

Correlation of ibuprofen bioavailability with gastrointestinal transit by scintigraphic monitoring of 171Er-labeled sustained-release tablets.

External gamma scintigraphy was used to monitor the gastrointestinal (GI) transit of radiolabeled sustained-release tablets containing 800 mg ibuprofen in eight fasted healthy volunteers. Ibuprofen serum concentrations were determined from blood samples drawn sequentially over a 24-hr period. Serum concentrations and related parameters were correlated to the position of the dosage form in the GI tract from the scintiphotos. The sustained-release tablets were radiolabeled intact utilizing a neutron activation procedure, by incorporating 0.18% of 170Er2O3 (enriched to greater than 96% 170Er) into the bulk formulation. After manufacture of the final dosage forms, the tablets were irradiated in a neutron flux (4.4 x 10(13) n/cm2.sec) for 2 min, converting the stable 170Er to radioactive 171Er (t1/2 = 7.5 hr). Each tablet contained 50 microCi of 171Er at the time of administration. The scintigraphy studies suggested that the greatest proportion of ibuprofen was absorbed from this dosage form while the tablet was in the large bowel. The dosage forms eroded slowly in the small bowel and appeared to lose their integrity in the large bowel. In vitro studies showed only minimal effects of the neutron irradiation procedure on the dosage form performance.

Single dose and steady-state pharmacokinetics of adinazolam after oral administration to man.

An aqueous solution containing 1 mg of adinazolam mesylate per ml was administered orally as a single dose (40 mg) and with loading doses followed by hourly doses such that final dose rates of 1, 2, and 3 mg h-1 were administered to steady-state. Four subjects exhibited linear steady-state kinetics, while the other four exhibited Michaelis-Menten kinetics, based on measurement by HPLC of both unchanged drug and the major N-demethyl metabolite. The drug is very rapidly absorbed and has an intrinsic clearance of total (bound + free) drug which averaged 2.14 l min-1 based on the steady-state data and 1.17 l min-1 based on the single dose data, but these means do not differ significantly. The apparent metabolite clearance, CLmc/fm (where fm = fraction of adinazolam converted to the N-demethyl metabolite), averaged 0.170 l min-1 based on steady-state data and 0.179 l min-1 based on single dose data and these means do not differ significantly. Pharmacokinetic parameters, such as these clearances, had large intersubject variations. Three types of bioavailabilities were estimated from the data.

Pharmacokinetics of flurbiprofen in man. I. Area/dose relationships.

Flurbiprofen pharmacokinetics were studied in 15 normal male subjects after four oral doses. Plasma levels of total (bound + free) drug were monitored for 48 h and urine was collected for 96 h after the doses. All subjects demonstrated linear relationships between administered dose and total flurbiprofen AUC, indicating that oral clearance is independent of dose for the dose range evaluated in this study. Urinary recovery data indicated that the efficacy of absorption was dose independent.

Michaelis-Menten elimination kinetics: areas under curves, steady-state concentrations, and clearances for compartment models with different types of input.

For single bolus administration, intermittent bolus administrations to steady-state, a single dose as a zero order input, intermittent zero order inputs to steady-state, and continuous zero order input to steady-state, and for both simple Michaelis-Menten elimination and parallel Michaelis-Menten and first order elimination, the appropriate equations are given for the areas, AUC 0-oo or AUC 0-tau, steady-state concentrations, and clearances. Some 20 new equations have been derived. For the case of first order input and Michaelis-Menten elimination, no solution is given but the effect of input rate on systemic availability is reported following some numerical integrations. The effect of slow input in reducing systemic bioavailability when Michaelis-Menten elimination kinetics are operative is stressed and the implications of this in the field of sustained-release medication mentioned.

A nonlinear physiologic pharmacokinetic model: I. Steady-state.

The two-compartment model of Rowland et al., (2) has been extended by replacing first order elimination with Michaelis-Menten elimination kinetics. All of the equations for steady-state concentrations and clearances for zero order (constant rate) input orally (into compartment #2) and intravenously (into compartment #1) are derived and reported. The steady-state concentration in compartment #1, following intravenous administration, is shown to be a nonlinear function of maximal velocity of metabolism, Vm, the Michaelis constant, Km, and liver blood flow, Q; and, following oral administration is dependent only upon Vm and Km and is independent of Q. However, oral bioavailability is a function of Vm, Km, and Q. The model allows physiologic pharmacokinetic interpretation of both linear and nonlinear data; and, together with simple modification of the model, can explain much observed pharmacokinetic data to date particularly for first-pass drugs. Future articles in the series will be concerned with single doses, evaluation of literature data in terms of the model, application of the theory in toxicology and in clinical pharmacokinetics and therapeutics.

Pharmacokinetics of ibuprofen in man IV: absorption and disposition.

Fifteen normal male volunteers received 400, 800, and 1200 mg doses of ibuprofen as 1, 2, or 3 tablets, respectively, in crossover fashion, then 420 mg in solution form during the fourth week. Plasma concentration of ibuprofen was measured by an HPLC method. Individual subject concentration-time (C,t) data following the solution were analyzed by two different methods, and results unequivocally indicated the open two compartment model with first order absorption. However, the computer fitting of both arithmetic and geometric mean concentrations led to a different model. A method was developed to obtain absorption data (fraction of drug absorbed, Fa, versus time) for a multicompartmental system from oral data alone, without intravenous data. The method assumes that Vp is constant intrasubject and that absorption is complete following administration of both the solution and tablets. The method was successfully applied to the ibuprofen tablet data. It was shown also that such a method is necessary to obtain ibuprofen absorption data since intrasubject variation of the microscopic rate constants k12, k21, and kel (as reflected by the intrasubject variation of the hybrid rate parameters lambda 1 and lambda 2 or beta and alpha) is of the same order of magnitude as intersubject variation. Absorption of ibuprofen from tablets was shown not to be simple first order as for the solution. The absorption profiles following one tablet were S-shaped, while those following 2 or 3 tablets had partial linear segments indicating zero order absorption.

Pharmacokinetics of ibuprofen in man--III: Plasma protein binding.

Plasma protein binding of ibuprofen was measured by equilibrium dialysis on 406 plasma samples collected from 15 normal volunteers following doses of 400, 800, and 1200 mg of ibuprofen as tablets (N = 102, 100, 104, respectively) and 420 mg as an aqueous solution (N = 100). Individual subject bound concentration at dialysis equilibrium (Cbd) vs. free concentration at dialysis equilibrium (Cfd) were well fitted via computer to the Scatchard equation with one class of binding sites. The binding capacity averaged 1231 microM (range 848-1658 microM), and the association constant averaged 1.76 X 10(5) M-1 (range 1.15 X 10(5) to 2.73 X 10(5) M-1). Distributional analysis was performed on the free fraction (fd) and bound/free ratios (Cbd/Cfd = 1/fd-1) at dialysis equilibrium for each treatment. Using pooled data of all four treatments, distributional analysis was also performed on the free fractions (f) and bound/free ratios (Cb/Cf = 1/f-1) corresponding to the plasma drug concentrations in blood as it was withdrawn from the subjects. The bound/free ratios were normally distributed, whereas the distributions of the free fractions were skewed towards higher values.

Pharmacokinetics of ibuprofen in man. I. Free and total area/dose relationships.

Ibuprofen kinetics were studied in 15 subjects after four oral doses. Plasma levels of both total and free ibuprofen were measured for 12 hr, and urine was collected for 48 hr after the doses. All subjects showed a nonlinear relationship between dose and total ibuprofen plasma AUC. Free ibuprofen plasma AUC, however, was linearly related to the dose, suggesting that oral clearance based on free drug was dose independent. Urinary recovery data indicated that efficiency of absorption was dose independent.