Clinical pharmacokinetics and drug metabolism of tazarotene: a novel topical treatment for acne and psoriasis.

Tazarotene (AGN 190168) is a new acetylenic retinoid which is effective for the topical treatment of patients with stable plaque psoriasis and mild to moderate acne vulgaris. Topical gel application provides direct delivery of tazarotene into the skin. At 10 hours after a topical application of 0.1% tazarotene gel to the skin of healthy individuals and patients with psoriasis, approximately 4 to 6% of the dose resided in the stratum corneum and 2% of the dose distributed to the viable epidermis and dermis. Tazarotene is rapidly hydrolysed by esterases to its active metabolite, tazarotenic acid. Tazarotenic acid does not accumulate in adipose tissue, but undergoes further metabolism to its sulfoxide and to other polar metabolites and is rapidly eliminated via both urinary and faecal pathways with a terminal half-life of about 18 hours. Percutaneous absorption is similar between healthy individuals and patients with facial acne, leading to plasma concentrations below 1 microg/L. The systemic bioavailability of tazarotene (measured as tazarotenic acid) is low, approximately 1% after single and multiple topical applications to healthy skin. In patients with psoriasis under typical conditions of use, systemic bioavailability increased during the initial 2 weeks of treatment from 1% (single dose) to 5% or less (steady state). The increased bioavailability is probably related to decreases in plaque elevation and scaling due to successful treatment, resulting in a less effective skin penetration barrier to tazarotene. Steady-state concentrations of tazarotenic acid are achieved within 2 weeks of topical treatment in both healthy and psoriatic skin types. The large variability in plasma concentrations observed in patients with psoriasis is probably because of the large differences in lesional skin condition, the amount of drug applied and the surface area of application. There was no significant drug accumulation in the body with long term treatment of patients with psoriasis. Topical administration of tazarotene requires dosages much smaller than those usually required for oral retinoids, such as isotretinoin, acitretin and etretinate, and it delivers the drug directly into the target skin tissues. The low systemic absorption and rapid systemic elimination of tazarotene and tazarotenic acid results in limited systemic exposure. Thus, topical tazarotene has a low potential for systemic adverse effects and is effective in the treatment of patients with acne and psoriasis.

Comparative tear concentrations over time of ofloxacin and tobramycin in human eyes.

The pharmacokinetic profiles of 0.3% ofloxacin and 0.3% tobramycin ophthalmic solutions after multiple administrations in the eyes of 160 healthy volunteers were evaluated. In human tears, ofloxacin and tobramycin were found to have terminal half-lives of 226 and 154 minutes, respectively. The mean residence time in the ocular tear fluid was 326 minutes for ofloxacin and 106 minutes for tobramycin. The mean duration of time that ofloxacin remained above the MIC90 value for five bacterial species evaluated was 605 minutes, compared with 251 minutes for tobramycin. The mean area under the inhibitory curve for the five bacterial species evaluated was greater for ofloxacin (2224) compared with tobramycin (1549). The duration of time above the MIC90 for ofloxacin was longer compared with tobramycin for gram-positive isolates. Overall, the pharmacokinetic and pharmacodynamic profiles of ofloxacin were superior to those of tobramycin for most parameters studied.

The urinary metabolic profile of metyrapone in the rat. Identification of two novel isomeric metyrapol N-oxide metabolites.

This study was designed to fully characterize the urinary metabolic profile of metyrapone following a 50 mg/kg ip dose to male Sprague-Dawley rats. Preliminary examination of alkaline dichloromethane extracts of urine by TLC and HPLC showed the absence of the intact drug, but the presence of moderate amounts of the two isomeric metyrapone mono-N-oxides, together with small amounts of metyrapol and the alpha-pyridone metabolite. These compounds have previously been reported as in vitro metabolites. Large amounts of two new metabolites of metyrapone were also observed and were conclusively identified as the isomeric metyrapol N-oxides by a combination of low- and high-resolution mass spectrometry. Quantitation by HPLC showed that metyrapol and the two metyrapone mono-N-oxides accounted for 4 and 10% of the dose, respectively. The two metyrapol mono-N-oxides accounted for more than 75% of the dose. These are novel metabolites not previously reported either as in vivo or in vitro metabolites.

Assay of metyrapone, metyrapol and the isomeric mono-N-oxides of metyrapone in biological fluids by high-performance liquid chromatography.

A sensitive high-performance liquid chromatographic (HPLC) method for the analysis of metyrapone [2-methyl-1,2-di-(3-pyridyl)-1-propanone], its reduced metabolite metyrapol and metyrapone mono-N-oxide metabolites in biological fluids is reported. These components were extracted into dichloromethane (2 x 5 ml) from alkalinised microsomal incubates, urine and blood (final pH about 12.5), or from cytosolic incubates at pH 7.4 (final aqueous volume 2-4 ml). Recoveries were in the range 70-100% under these conditions. The intact drug and metabolites were separated by reversed-phase HPLC with ultraviolet detection at 261 nm. All calibration curves were linear (correlation coefficient greater than 0.997). For the analysis of hepatic microsomal or cytosolic incubates, the coefficient of variation was less than 10% for samples over the range 2.5-250 nmol/ml N-oxides and 10-250 nmol/ml metyrapol. Measurement of metyrapone and metyrapol in rat blood (0.25-ml sample volume) was linear in the ranges 4.4-265 and 26-263 nmol/ml, respectively, the lower concentration being the limit of detection. The coefficient of variation was less than 20% for samples over the ranges tested for both these compounds. The N-oxide metabolites were not detectable in blood using this assay, their concentrations being below the limit of detection.

The uptake and efflux of doxorubicin by a sensitive human bladder cancer cell line and its doxorubicin-resistant subline.

The uptake and efflux of doxorubicin (Dox) were investigated in a human bladder cancer cell line (UM-UC-6) and in a multi-drug resistant (mdr) subline (UM-UC-6Dox). Unlike previous reports, the initial uptake kinetics of Dox, and its accumulation and retention to steady-state were modelled mathematically. Cells were incubated with Dox and the amount of Dox in the cellular and medium phases was measured by a specific HPLC method. When monitored for 1 min from 0.02 microM to 25 microM Dox, the uptake was very rapid but was significantly faster in the resistant cell line. The initial rate of uptake at t = 0 followed Michaelis-Menten kinetics yielding Vmax values (the maximal rate of uptake) of 15.0 +/- 1.7 and 12.9 +/- 1.2 nmol/10(6)/min and Km (rate at Vmax/2) of 25.2 +/- 4.7 and 16.4 +/- 2.9 microM for UM-UC-6 and UM-UC-6Dox, respectively. There was no metabolism of Dox by keto-reduction or reductive hydrolysis. At 1.0 microM the uptake of Dox to steady-state was biexponential but there was no difference in total cellular Dox concentration between the two cell lines at equilibrium. A 3 compartment sequential closed model was fitted yielding significantly different values for the intercompartmental and hybrid rate constants, indicating altered intracellular distribution in resistant cells. Verapamil (10 microM), trifluoperazine (10 microM) or Tween 80 (0.005%) had no effect on the uptake or efflux of Dox. The UM-UC-6Dox line appeared to show atypical mdr characteristics since net drug accumulation was not lowered and classic P-glycoprotein inhibitors were not effective. The primary mechanism of Dox resistance is not enhanced metabolism or lowered intracellular concentrations.

The pharmacokinetics of pirtenidine in the rat and dog.

1. Pharmacokinetic studies on the topical antimicrobial agent, pirtenidine, have been conducted in male Sprague-Dawley rats and beagle dogs, using a validated h.p.l.c. method with u.v. detection to measure the drug in plasma. 2. Following a single i.v. bolus dose to the rat (equivalent to 1.35 mg base/kg) or dog (equivalent to 0.23 mg base/kg), the drug was extensively distributed with an apparent volume of distribution of 8.61/kg in rat and 3.31/kg in dog. Clearance was high (rat 2.71/h/kg; dog 1.51/kg) which resulted in a short terminal half-life in both species (2.2 and 1.5 h respectively). 3. Following a single oral dose to rats (equivalent to 4.5 mg base/kg) plasma pirtenidine concentrations were generally below the minimum quantifiable level of the analytical method (1 ng/ml). A maximum possible bioavailability of 0.3% was estimated. 4. After administering the same oral dose to dogs plasma concentrations rose slowly (t 1/2 abs = 1.2 h) to a peak (49.7 ng/ml) at 5.0 h post-dose. The terminal elimination half-life was 2.1 h. The absolute bioavailability was 10%.

The relationship between the pharmacokinetics of amrinone in the marmoset and platelet effects.

The pharmacokinetic characteristics of amrinone have been studied in six female marmosets following oral administration of 1, 12.5, 25, 50 and 75 mg.kg-1 and an intravenous dose of 1mg.kg-1. The mean plasma AUC0 infinity was determined at each dose level; the values obtained were 2.5, 18.7, 33.9, 103 and 312 micrograms.h.ml-1 for the oral doses of 1, 12.5, 25, 50 and 75 mg.kg-1 respectively and 1.9 micrograms.h.ml-1 for the intravenous dose of 1mg.kg-1. Mean maximum observed plasma concentrations were 0.6, 7.1, 11.7, 23.7 and 40.0 micrograms.ml-1 respectively following oral doses. Over the range 1 to 50 mg.kg-1 the AUC0 infinity was linear; at 75 mg.kg-1 the AUC0 infinity was disproportionately greater. Elimination appeared to be first order over the dose range 1 to 50 mg.kg-1 and the t1/2 in the marmoset was approximately 1 to 3 hours over this dose range. The plasma levels achieved are discussed in relation to the observed effects on the platelet population in this species following chronic administration at high dose levels.