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 , V m , the Michaelis constant , K m , and liver blood flow , Q; and, following oral administration is dependent only upon V m and K m and is independent of Q. However, oral bioavailability is a function of V m , K m , 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 .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45033/1/10928_2005_Article_BF01073657.pd

Bioavailability assessment of topical delivery systems: effect of inter-subject variability on relative in vitro deliveries of minoxidil and hydrocortisone from solution and ointment formulations

The present study demonstrates that in vitro comparisons of delivery vehicles are reliable as long as one performs the studies on skin samples taken from the same cadaver section of skin. The in vitro rates of delivery of minoxidil and hydrocortisone from an ointment and a propylene glycol/ethanol/water vehicle through skin sections taken from the same and different cadaver abdomens are specifically compared. When tested on skins from 8 human cadavers, the fluxes of minoxidil suspended in the ointment ranged from 0.37 x 10-5 mg/cm2/h to 9.2 x 10-5 mg/cm2/h, a 25-fold spread, and the fluxes of minoxidil from the propylene glycol/ethanol/water vehicle ranged from 1.25 x 10-5 mg/cm2/h to 18.7 x 10-5 mg/cm2/h, a 15-fold spread. However, when the ratios of fluxes between these two formulations were calculated for individual subjects, the values ranged from 1.3 to 3.5 (only a 3-fold spread). Four human cadaver sections were used to evaluate the delivery of hydrocortisone. The flux values ranged from 696 to 1335 cpm/cm2/h for the ointment and 946 to 1291 cpm/cm2/h for the propylene glycol/ethanol/water vehicle (up to a 2-fold spread). When the ratios of fluxes between these two formulations were calculated for each individual subject, the values ranged from 0.96 to 1.39. The results with these two compounds suggest that even in the unavoidable presence of large inter-subject variations in the cadaver skin, the influence of vehicle on drug delivery performance can be determined. In addition to these findings concerning intra-subject variability, it was observed that the flux of minoxidil from the ointment attains a steady-state after an initial lag period of between 6 and 8 h but steady delivery is not apparent for the minoxidil solution, suggesting that for the solution formulation the thermodynamic activity of. the drug changes markedly as the experiment proceeds. No comparable curvature is seen for the hydrocortisone solution presumably because its thermodynamic activity is little changed during the vehicle's evaporation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28049/1/0000488.pd

Bioavailability assessment of topical delivery systems: Effect of vehicle evaporation upon in vitro delivery of minoxidil from solution formulations

Two sets of in vitro permeation experiments were carried out to study the topical delivery of minoxidil as a function of its thermodynamic activity in the hydroalcoholic vehicles applied to the skin. Franz diffusion cells were employed with human cadaver skin membranes. The delivery of minoxidil of different concentrations (0.5%, 1%, 2%, 3%, 4% and 5%) from simple solutions in a fixed composition of propylene glycol/water/ethanol (20.0:63.2:16.8) was determined. The flux of minoxidil increased systematically from 0.5% to 3% concentration and then fell back abruptly at the 5% concentration. The maximum in the flux seen at the intermediate concentrations (3-4%) opened the possibility that the drug might be crystallizing upon evaporation of the volatile components of the vehicle. It was discovered that the 3% and even the 4% minoxidil concentration supported a relatively persistent supersaturation but at 5% the drug crystallized soon after its application. These phenomena were confirmed by observing crystal formation of minoxidil solutions under the microscope. It was found by following the weight of minoxidil solutions applied to a glass surface that 65% of the weight of the solution vehicle evaporated after the first 30 min and about 75% evaporated after 2 h. For the 5% minoxidil solution crystals were evident within 6-7 min. By way of contrast, no crystals were evident in the 3% minoxidil solution after 2 h. Secondly, since the evaporation of the volatile ethanol and water components of the vehicle play an important role in delivery permeation profiles of minoxidil (1%, 2%, 3% and 5%) from solutions of propylene glycol, water and ethanol prepared so as to contain a fixed amount of propylene glycol per unit weight of minoxidil were obtained. There was no significant difference in the flux of minoxidil when its concentration in the non-volatile component, propylene glycol, was kept constant.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27716/1/0000104.pd

Bioavailability assessment of topical delivery systems: in vitro delivery of minoxidil from prototypical semi-solid formulations

An in vitro technique has been developed for evaluating the delivery performance of topical semi-solid formulations. A thin and uniform layer of formulation was applied in facsimile to actual usage conditions by troweling the vehicle across a thin. circular copper template (200 [mu]m in thickness). Approximately 30-45 mg of an oil-in-water cream, a water-in-oil cream or an ointment, each containing a range of concentrations of minoxidil, were applied over human cadaver skin within a defined circular area of 1.54 cm2. The rates of permeation of minoxidil from these formulations were determined by finite dose diffusion experiments. For formulations containing 2% minoxidil, the flux from the w/o cream tested was about 4 times higher than fluxes from the o/w cream and the ointment. Even though all w/o formulations were initially saturated with drug, the flux of minoxidil from these creams increased as the concentration of minoxidil was increased from 0.5% to 2%. In contrast, the delivery rates from the o/w cream and the ointment did not appear to be dependent on the minoxidil concentration applied (0.5-2%). Under the operative experimental conditions, the percent coefficients of variation of flux of minoxidil from these formulations were less than 20%. To achieve this low level of variability, the skin samples were all obtained from the same cadaver abdomen. If one assumes that the efficacy of a particular formulation is dependent on the ability of the drug to be released from the vehicle and diffuse through the skin, the studies show that the nature of the vehicle can profoundly affect delivery even when excess solid drug is present. They also indicate that reliable in vitro comparisons of drug delivery are possible as long as one performs the studies on skin samples taken from the same section of skin.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28086/1/0000532.pd

Pharmacokinetics of ibuprofen in man IV: Absorption and disposition

Fifteen normal male volunters 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 , F a , versus time) for a multicompartmental system from oral data alone, without intravenous data. The method assumes that V p 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 k 12 , k a21 , and k el ( as reflected by the intrasubject variation of the hybrid rate parameters λ 1 and λ 2 or Β and a) 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 .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45032/1/10928_2005_Article_BF01062664.pd

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 < 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 < 0.01). These results suggest that gastric emptying effects are one important way in which absorption of drugs can be affected by meal intake.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41574/1/11095_2004_Article_305207.pd

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 (C bd ) vs. free concentration at dialysis equilibrium (C fd ) were well fitted via computer to the Scatchard equation with one class of binding sites. The binding capacity averaged 1231 μM (range 848–1658 μM), and the association constant averaged 1.76 × 10 5 M −1 (range 1.15 × 10 5 to 2.73 × 10 5 M −1 ). Distributional analysis was performed on the free fraction (f d ) and bound/free ratios (C bd /C fd =1/f d −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 (C b /C f=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.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45031/1/10928_2005_Article_BF01062206.pd

Metabolic syndrome is associated with similar long-term prognosis in non-obese and obese patients. An analysis of 45 615 patients from the nationwide LIPIDOGRAM 2004-2015 cohort studies

Aims We aimed to evaluate the association between metabolic syndrome (MetS) and long-term all-cause mortality. Methods The LIPIDOGRAM studies were carried out in the primary care in Poland in 2004, 2006 and 2015. MetS was diagnosed based on the National Cholesterol Education Program, Adult Treatment Panel III (NCEP/ATP III) and Joint Interim Statement (JIS) criteria. The cohort was divided into four groups: non-obese patients without MetS, obese patients without MetS, non-obese patients with MetS and obese patients with MetS. Differences in all-cause mortality was analyzed using Kaplan-Meier and Cox regression analyses. Results 45,615 participants were enrolled (mean age 56.3, standard deviation: 11.8 years; 61.7% female). MetS was diagnosed in 14,202 (31%) by NCEP/ATP III criteria, and 17,216 (37.7%) by JIS criteria. Follow-up was available for 44,620 (97.8%, median duration 15.3 years) patients. MetS was associated with increased mortality risk among the obese (hazard ratio, HR: 1.88 [95% CI, 1.79-1.99] and HR: 1.93 [95% CI 1.82-2.04], according to NCEP/ATP III and JIS criteria, respectively) and non-obese individuals (HR: 2.11 [95% CI 1.85-2.40] and 1.7 [95% CI, 1.56-1.85] according to NCEP/ATP III and JIS criteria respectively). Obese patients without MetS had a higher mortality risk than non-obese patients without MetS (HR: 1.16 [95% CI 1.10-1.23] and HR: 1.22 [95%CI 1.15-1.30], respectively in subgroups with NCEP/ATP III and JIS criteria applied). Conclusions MetS is associated with increased all-cause mortality risk in non-obese and obese patients. In patients without MetS obesity remains significantly associated with mortality. The concept of metabolically healthy obesity should be revised