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.

Oral contraceptive effects on methylprednisolone pharmacokinetics and pharmacodynamics.

OBJECTIVE: Oral contraceptive (OC) steroids alter the disposition of numerous drugs, including corticosteroids. We investigated the pharmacokinetics and pharmacodynamics of methylprednisolone. METHODS: Twelve women (six women used OC steroids and six women did not) received intravenous methylprednisolone (0.6 mg/kg ideal body weight). Methylprednisolone disposition was assessed from plasma concentrations. Pharmacodynamic parameters measured were plasma cortisol, whole blood histamine (reflecting basophils), and blood helper T lymphocytes. RESULTS: Methylprednisolone clearance was significantly decreased in the women who used OC steroids (0.298 versus 0.447 L/hr/kg), resulting in a longer elimination half-life (2.20 versus 1.72 hours). With use of indirect response models, significant differences were observed with the cortisol and basophil responses. A larger value for the concentration that inhibits the zero-order production rate by 50% (0.37 versus 0.11 ng/ml) was observed in the women who used OC steroids for suppression of cortisol secretion, indicating less sensitivity to the suppressive effects of methylprednisolone. Greater net suppression of basophils was observed in the users of OC steroids (area under the response curve, 694 versus 401 ng x hr/ml). No differences were observed for helper T-cell responses. CONCLUSION: OC steroids appear to inhibit methylprednisolone metabolism. However, mixed changes in several responses occur, indicating that women can probably receive similar doses of methylprednisolone irrespective of OC steroid use.

PIP: At the Buffalo General Hospital in New York, researchers randomly assigned 6 healthy, nonobese women, 30-36 years old and using a triphasic oral contraceptive (OC) (Triphasil 28, Wyeth-Ayerst Laboratories), to either the baseline phase group or the group receiving an intravenous bolus of methylprednisolone sodium succinate at a dose of 0.6 mg/kg ideal body weight during the 2-week period after ovulation (i.e., luteal phase). These women were compared with 6 other women who did not use OCs but did receive the same dose of methylprednisolone. The purpose was to determine whether the adrenosuppressive, anti-inflammatory, and immunosuppressive effects of methylprednisolone differ in OC users. OC users experienced slower clearance of methylprednisolone (33% slower) than controls. This slower clearance rate contributed to a longer elimination half-life for methylprednisolone (2.2 vs. 1.72 hours; p 0.05). OC users also had a rate of slower elimination of cortisol than controls (0.180 vs. 0.276 hr-1; p 0.05). They had higher mean cortisol levels than controls (136 vs. 65 ng/ml). Women who used OCs for suppression of cortisol secretion had a larger value for the concentration of cortisol that suppresses the zero-order production rate by 50% (0.37 vs. 0.11 ng/ml; p 0.05), suggesting a decreased sensitivity to the effects of methylprednisolone on cortisol suppression. OC users experienced a greater net suppression of basophils at drug effect than at baseline. Methylprednisolone appeared to have no effect on helper T-cell responses. These findings suggest that OCs inhibit methylprednisolone metabolism. Since there were inconsistent changes in several responses, women can likely receive similar doses of methylprednisolone irrespective of OC use.

Gender-based effects on methylprednisolone pharmacokinetics and pharmacodynamics.

The pharmacokinetics and selected pharmacodynamic responses to methylprednisolone were investigated in six men and six premenopausal women after a dose of 0.6 mg/kg ideal body weight. Women (luteal phase) exhibited a greater methylprednisolone clearance (0.45 versus 0.29 L/hr/kg) and shorter elimination half-life (1.7 versus 2.6 hours) than men. The volume of distribution of methylprednisolone was similar when normalized for ideal body weight. Pharmacodynamic models were used to examine the methylprednisolone suppressive effects on cortisol secretion and basophil and helper T lymphocyte trafficking. A significantly smaller 50% inhibitory concentration (IC50) value (0.1 versus 1.7 ng/ml) was seen in the women for suppression of cortisol secretion, indicating increased sensitivity. However, the area under the concentration-time curve of effect was similar for both groups. The IC50 values for effects of methylprednisolone on basophil trafficking related to estradiol concentrations in a log-linear fashion in women, with increased sensitivity found at higher estradiol concentrations. Men displayed a greater 24-hour net suppression in blood basophil numbers, but no difference was observed in net cortisol and helper T lymphocyte suppression between the sexes. These findings suggest that methylprednisolone dosages should be based on ideal body weight. Although women are more sensitive to methylprednisolone as measured by cortisol suppression, they eliminate the drug more quickly, generally producing a similar net response.

Gender and pramipexole effects on levodopa pharmacokinetics and pharmacodynamics.

The authors studied the pharmacokinetics of levodopa (LD) with and without pramipexole (PPX) in men and postmenopausal women with PD. Patients on stable dose of carbidopa/LD were randomized to receive escalating doses of placebo or PPX over 7 weeks. LD and PPX pharmacokinetics were performed after a single test dose 25/100 of carbidopa/LD, before initiation of PPX or placebo, at 1.5 mg/d and 4.5 mg/d of PPX or placebo. Compared to men, women had greater LD bioavailability. PPX did not alter LD bioavailability, and PPX pharmacokinetics were equivalent in men and women.

Multiple-dose cimetidine administration does not influence the single-dose pharmacokinetics of quinapril and its active metabolite (CI-928).

The potential effect of cimetidine on the pharmacokinetic profiles of quinapril and its active metabolite CI-928 was evaluated in eight healthy volunteers. Each subject received a single 40-mg quinapril dose on days 1 and 12 and cimetidine 300 mg four times daily on days 8 through 13. Serial blood and urine samples were collected for assay of quinapril and CI-928 concentrations. No statistically significant differences were observed in quinapril or CI-928 Cmax, tmax, AUC(0-infinity), beta, or percent of dose excreted in urine values for quinapril administered alone and in combination with cimetidine. Therefore, multiple-dose cimetidine administration does not influence the single-dose pharmacokinetics of quinapril and its active metabolite, CI-928, in healthy volunteers.

Pharmacokinetics of cefpodoxime proxetil in healthy young and elderly volunteers.

The influence of age on the pharmacokinetics of cefpodoxime was evaluated in 12 elderly (ages 65-85 years) and 12 weight- and sex-matched young (ages 20-33 years) subjects, each of whom received two cefpodoxime proxetil 200-mg tablets every 12 hours for 14.5 days. Serial blood samples and urine were collected after the first dose on day 1, after the morning dose on day 8, and after the last (morning) dose on day 15. Plasma and urine samples were assayed for cefpodoxime concentrations using HPLC methods. Within each age group, mean pharmacokinetic parameters determined on day 1 were similar to corresponding values on days 8 and 15, indicating that cefpodoxime does not accumulate after twice-daily dosing of cefpodoxime proxetil. Based on this result, parameters were pooled across days in each age group. No significant differences were observed between healthy and elderly volunteers in area under the plasma concentration-time curve for the 12-hour dosing interval, peak plasma concentration, or time to peak concentration. Mean urinary excretion and renal clearance of cefpodoxime were significantly lower in elderly subjects. Differences in renal clearance were attributed to the corresponding age-related reduction that was noted in creatinine clearance values, whereas the lower urinary excretion of cefpodoxime probably reflected slightly reduced systemic drug absorption in the elderly. Differences in these parameters between groups were less than 30%, and were unlikely to be of clinical importance. The data indicate that dose adjustment of cefpodoxime in elderly subjects having normal (age-adjusted) creatinine clearance values is not required.

Pilot study of the pharmacokinetics of methylprednisolone after single and multiple intravenous doses of methylprednisolone sodium succinate and methylprednisolone suleptanate to healthy volunteers.

The pharmacokinetics of methylprednisolone were evaluated in 29 healthy volunteers after multiple intravenous doses of methylprednisolone sodium succinate or the novel prodrug, methylprednisolone suleptanate. Subjects were assigned randomly to one of four treatment groups (40, 100, 250, or 500 mg) and then randomly assigned to receive either the sodium succinate or suleptanate prodrugs. Doses were administered every 6 hours for 48 hours. Plasma and urine were assayed for methylprednisolone and unchanged prodrug using HPLC methods. Methylprednisolone pharmacokinetics exhibited both a dose and time dependency, which was similar for administration of both prodrugs. After first-dose administration, mean clearance increased from 19.5 L/hr for 40-mg doses to 27.7 L/hr after 500-mg doses of the sodium succinate ester, and from 20.1 to 31.7 L/hr after the suleptanate ester. After multiple dosing, mean clearance values increased from 31.1 to 44.7 L/hr for sodium succinate dosing, and from 31.5 to 46.0 L/hr for suleptanate dosing. Apparent systemic clearance values determined after multiple dosing were 1.5- to 1.8-fold greater than corresponding first-dose values. No dependence on time was apparent for any prodrug pharmacokinetic parameter. These data suggest that the dose dependency of methylprednisolone pharmacokinetics is related to dose-dependent prodrug hydrolysis, whereas the time dependence possibly reflects auto-induction of methylprednisolone metabolism. Based on comparison of methylprednisolone pharmacokinetic parameters derived for each prodrug, methylprednisolone suleptanate resulted in a faster and slightly more efficient conversion to methylprednisolone than methylprednisolone sodium succinate.

Influence of food on the pharmacokinetics of quinapril and its active diacid metabolite, CI-928.

A randomized two-way crossover study was conducted in 12 healthy volunteers to assess the effect of food on the pharmacokinetics of quinapril (CI-906) and its active metabolite, CI-928, after quinapril dosing. Forty-milligram oral quinapril doses were administered in a fasted or a fed state with a one-week washout period between treatments. No significant treatment differences were observed in quinapril and CI-928 values for maximum plasma concentration, area under the plasma concentration-time curve, or percentage of dose excreted in the urine. Small but significant increases of less than 0.5 hour in quinapril and CI-928 tmax values were observed after consumption of food. The pharmacokinetic profiles of quinapril and CI-928 were not significantly altered by the administration of food.

Relative and absolute bioavailability of prednisone and prednisolone after separate oral and intravenous doses.

A randomized, four-way cross-over study was conducted in eight healthy male volunteers to determine the relative and absolute bioavailability of prednisone (PN) and prednisolone (PL). PN and PL were administered as single, oral 10-mg tablet doses and as 10-mg zero-order 0.5-hour intravenous infusions. Comparable mean PN and PL maximum plasma concentrations (Cmax), times for Cmax, areas under the plasma concentration-time curves (AUC), and apparent elimination rate constants between tablet treatments demonstrated that PN and PL tablets were bioequivalent. Absolute bioavailability (F) determinations based on plasma PL concentrations were independent of which IV treatment was used as reference and indicated complete systemic availability of PL from both PN and PL tablets. However, F based on plasma PN data was contradictory. Using IV PN as reference, approximately 70% systemic availability was observed from both tablets, whereas using IV PL as reference, systemic availability was greater than unity. PN and PL are model compounds that exemplify the difficulties involved in accurately determining the relative and absolute bioavailability of substances that undergo reversible metabolism.

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.

Absorption of flurbiprofen through human buccal mucosa.

The absorption of flurbiprofen through human buccal mucosa was studied after 25 mL of a 2.5-mg/mL solution (pH 4) of the drug in a cosolvent mixture (ethanol 95%:glycerin:propylene glycol:0.3 M sodium acetate buffer, 10:40:30:20) was held and circulated in the mouth for 5 min in a "buccal absorption test." The results were compared with those obtained after oral administration of 25 mL of a solution (pH 7) of sodium flurbiprofen having the same concentration. Twelve subjects participated in the crossover study. After the buccal treatment, mean Cmax and Tmax values were 0.751 micrograms/mL and 41 min, respectively. Average Cmax and Tmax values after the oral treatment were 10.8 micrograms/mL and 32 min, respectively. Mean dose-corrected AUCs were 0.0854 and 0.811 (micrograms.h/mL)/mg for the buccal and the oral treatments, respectively. The absorption kinetics after the buccal treatment were evaluated using the Exact Loo-Riegelman Method (ELRM). Buccal plasma flurbiprofen concentration-time data for 11 subjects were very well fitted by reconstructed curves using ka and the lag-time obtained from ELRM analysis of the buccal data and the disposition parameters obtained from the oral data. These results strongly support the concept of intrasubject constancy of flurbiprofen disposition parameters. Analysis, by ELRM, of the plasma concentration-time data obtained after the buccal treatment indicated first-order absorption, with a mean ka value of 3.9 +/- 2.2 h-1. This value was significantly different (0.05 greater than p greater than 0.02) from the ka after oral treatment (7.89 +/- 5.2 h-1), obtained from the triexponential fitting of the oral plasma data.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug and vehicle deposition from topical applications: use of in vitro mass balance technique with minoxidil solutions.

The disposition of minoxidil and propylene glycol from topical solutions was measured by using an in vitro mass balance technique. The experimental approach included assessment of the following compartments of the skin and the diffusion cell as a function of time: (1) donor compartment; (2) hairless mouse skin surface, epidermis, and dermis; and (3) receiver compartment. Excellent mass balance was achieved for minoxidil at three doses. However, the recovery of propylene glycol depended on both application volume and time. The experiment involving the evaporation of propylene glycol and water from the propylene glycol:ethanol:water (20:60:20, v/v) mixture, which was placed in the well of a tissue culture plate at room temperature and 37 degrees C, substantiated the loss of vehicles to the air. When a thin application of 20 microL/cm2 was used, 60% of the propylene glycol was unaccounted for after 16 h. The evaporation of propylene glycol concentrated the solution to supersaturation, precipitated out the drug, and then stabilized the thermodynamic activity of the drug in the vehicle. The amount of formulation applied influences the rate of concentration and, thus, the time at which minoxidil precipitates. The precipitation limits the amount of minoxidil that can be absorbed and leads to poor percutaneous absorption of drug from the formulation.

The nonlinear pharmacokinetics of prednisone and prednisolone. II. Plasma protein binding of prednisone and prednisolone in rabbit and human plasma.

The protein binding characteristics of prednisone and prednisolone were determined in human and rabbit plasma and in a 4.7 per cent human serum albumin (HSA) solution. The influence of prednisolone on prednisone binding in human plasma was also examined. Prednisolone exhibited nonlinear binding and prednisone linear binding characteristics in both human and rabbit plasma. Prednisone binding was not influenced by the presence of prednisolone. Prednisone binding to HSA was linear but to a degree substantially lower than observed in human plasma, suggesting the possibility that prednisone binds to other proteins in human plasma. The results support the hypothesis that the protein binding characteristics of prednisone and prednisolone do not explain the reported nonlinear pharmacokinetics of prednisone.

The non-linear pharmacokinetics of prednisone and prednisolone. III. Experiments using the rabbit as an animal model.

Intravenous zero order infusions were administered to New Zealand white rabbits. In a pilot study using one rabbit, prednisone and prednisolone clearance values increased with increase in either prednisone or prednisolone infusion rates. In the second study, prednisone was infused until both prednisone and prednisolone achieved steady-state concentrations. In the third study, prednisone was infused until only prednisone achieved steady-state concentrations. The results of the three experiments support the use of a non-linear reversible metabolism model to describe the pharmacokinetic relationship between prednisone and prednisolone.

The non-linear pharmacokinetics of prednisone and prednisolone. I. Theoretical.

Three simple linear and three simple non-linear pharmacokinetic models are presented which incorporate the reversible metabolism that occurs between prednisone and prednisolone. Under steady-state conditions it is possible to not only distinguish between the linear and non-linear models but also to determine which particular model of each group applies to a given set of data. While the non-linear conversion of prednisolone to prednisone is important in explaining the pharmacokinetics of prednisone in all three non-linear models, the same is not true for prednisolone.

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.

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.

Co-infection with Legionella pneumophila and Pneumocystis carinii in a patient with chronic lymphocytic leukemia.

A patient with chronic lymphocytic leukemia was found to have pneumonitis caused by a simultaneous Pneumocystis carinii and Legionella pneumophila infection. Although both microorganisms frequently cause pulmonary infections in immunocompromised patients, co-infection has not been reported. This patient responded to antimicrobial therapy, but superinfection with Candida albicans led to his death. As there are numerous infective and noninfective causes of pneumonia in such patients, this case illustrates that the identification of a single etiologic agent does not obviate the search for other potential causes.