Disposition in humans of racemic picenadol, an opioid analgesic

Racemic picenadol is being tested clinically as an analgesic. The (+)-enantiomer of picenadol is an opioid agonist and the (-)-enantiomer is a weak agonist/antagonist. The disposition of racemic [14C] picenadol was studied in healthy men after a single dose was administered im (N = 3) and orally (N = 5). After the dose, virtually none of the radioactivity that appeared in blood was associated with the red cells. In plasma, approximately 4% of the radioactivity was attributable to the parent drug, the remainder being picenadol glucuronide (approximately 35%) and other metabolites. The t1/2 for total radioactivity was 6 hr, that for the unchanged drug was 3.5 hr. Picenadol was present in plasma almost exclusively as the (+)-enantiomer. However, after incubation with glucuronidase and sulfatase, plasma contained 2 to 4 times more (-)- than (+)-picenadol, indicating that more conjugated (-)-picenadol than conjugated (+)-picenadol was in the plasma. After im and oral administration of [14C]picenadol, plasma levels of radioactivity were generally 10 and 70 times higher than those in saliva, respectively. More than 90% of the administered radioactivity was excreted in the urine, mostly as picendol glucuronide, and lesser amounts of picenadol sulfate and N-desmethylpicenadol sulfate. Only about 1% of the administered dose of picenadol appeared unchanged in urine. The disposition of racemic picenadol in humans was stereoselective, the (-)-picenadol apparently being metabolized preferentially over the (+)-enantiomer. This finding was of particular interest in view of the dissimilar pharmacologic activities of the enantiomers.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical pharmacokinetics of pinacidil, a potassium channel opener, in hypertension

Pinacidil is a potassium channel opener that decreases blood pressure by reducing peripheral arterial resistance. In two multicenter trials, we studied the concentrations and apparent clearance of pinacidil (406 patients) and concentrations of its pyridyl-N-oxide metabolite (147 patients). Responding patients had plasma samples collected hourly for 12 hours on 2 occasions after weeks to months of treatment. Pinacidil dose was titrated from 12.5 to 75 mg b.i.d. The peak concentration of pinacidil and N-oxide and the area under the concentration-time curve (AUC) were proportional to the dose of pinacidil, with an average pinacidil concentration of 268 micrograms/L (1.02 microM) and N-oxide concentration of 172 micrograms/L (0.65 microM) for every 1 mg/kg pinacidil administered. Clearance of pinacidil (Clp = Dose/AUC) was 31 L/hr in patients younger than 45 years and 27 L/hr in those older than 60. Clp was significantly smaller in white patients compared with other races (Clp = 28 vs. 34 L/hr). Clp was significantly less in patients taking hydrochlorothiazide (27 vs. 31 L/hr) and greater in smokers (33 vs. 29 L/hr). Concomitant propranolol use did not influence Clp.     

Atomoxetine hydrochloride: clinical drug-drug interaction prediction and outcome

In the studies reported here, the ability of atomoxetine hydrochloride (Strattera) to inhibit or induce the metabolic capabilities of selected human isoforms of cytochrome P450 was evaluated. Initially, the potential of atomoxetine and its two metabolites, N-desmethylatomoxetine and 4-hydroxyatomoxetine, to inhibit the metabolism of probe substrates for CYP1A2, CYP2C9, CYP2D6, and CYP3A was evaluated in human hepatic microsomes. Although little inhibition of CYP1A2 and CYP2C9 activity was observed, inhibition was predicted for CYP3A (56% predicted inhibition) and CYP2D6 (60% predicted inhibition) at concentrations representative of high therapeutic doses of atomoxetine. The ability of atomoxetine to induce the catalytic activities of CYP1A2 and CYP3A in human hepatocytes was also evaluated; however, atomoxetine did not induce either isoenzyme. Based on the potential of interaction from the in vitro experiments, drug interaction studies in healthy subjects were conducted using probe substrates for CYP2D6 (desipramine) in CYP2D6 extensive metabolizer subjects and CYP3A (midazolam) in CYP2D6 poor metabolizer subjects. Single-dose pharmacokinetic parameters of desipramine (single dose of 50 mg) were not altered when coadministered with atomoxetine (40 or 60 mg b.i.d. for 13 days). Only modest changes (approximately 16%) were observed in the plasma pharmacokinetics of midazolam (single dose of 5 mg) when coadministered with atomoxetine (60 mg b.i.d. for 12 days). Although at high therapeutic doses of atomoxetine inhibition of CYP2D6 and CYP3A was predicted, definitive in vivo studies clearly indicate that atomoxetine administration with substrates of CYP2D6 and CYP3A does not result in clinically significant drug interactions.     

The effect of colestipol hydrochloride on the bioavailability and pharmacokinetics of clofibrate

Since it has been reported by several authors that colestipol HCl and clofibrate have an additive effect in lowering serum cholesterol levels, it was felt advisable to evaluate the blood levels of clofibrate when given simultaneously with colestipol HCl to see whether there was any evidence for drug interaction between the two products that might dictate a need for separation of their administration time. After concomitant single-dose administration, the serum p-chlorophenoxyisobutyric acid levels, bioavailability parameters, and pharmacokinetic parameters investigated provided no evidence for an interaction and suggested that colestipol and clofibrate can be administered concomitantly or at separated in tervals according to whichever dosage regimen is deemed advisable by the physician.     

Sensitive, specific radioimmunoassay for quantifying pergolide in plasma.

Pergolide, a synthetic ergoline with potent dopaminergic activity, is used to treat Parkinson disease. The low plasma concentrations of pergolide achieved during therapy complicate the development of a method for its analysis. Because radioimmunoassay successfully measures other structurally related ergolines in physiological fluids, we undertook the development of a radioimmunoassay of pergolide. The detection limit of the radioimmunoassay is 21 ng/L with an optimal working range from 100 to 1000 ng/L. We maximized assay specificity by using a monoclonal antibody that displayed low cross-reactivity with pergolide sulfoxide, a major metabolite found in animals. The radioimmunoassay has performed acceptably for > 2 years during toxicology studies with rats and rhesus monkeys and in clinical studies involving patients with Parkinson disease. We consider the radioimmunoassay a valid method for quantifying therapeutic concentrations of pergolide in plasma.     

Antibiotic batch certification and bioequivalence.

All antibiotics marketed in the United States must undergo batch certification by the Food and Drug Administration. It is often assumed that the different brands of a particular antibiotic that pass in vitro batch certification tests have equal in vivo bioavailability. The fallacy of this assumption is clearly supported for commercially available lots of tetracycline hydrochloride that had passed batch certification tests yet had different serial serum concentrations.     

Effect of probenecid on the pharmacokinetics of moxalactam.

The effects of probenecid on the pharmacokinetics of moxalactam were studied in normal volunteers administered a 2-min l-g intravenous infusion. The results showed that probenecid did not alter the plasma or urinary concentrations of moxalactam, its apparent volume of distribution, plasma elimination half-life, elimination rate constant, or plasma and renal clearances. Therefore, moxalactam appears to be eliminated primarily by the kidney via glomerular filtration.     

From the Cover: Persistent impacts of West Nile virus on North American bird populations

Since its introduction to North America in 1999, West Nile virus (WNV) has had devastating impacts on native host populations, but to date these impacts have been difficult to measure. Using a continental-scale dataset comprised of a quarter-million birds captured over nearly two decades and a recently developed model of WNV risk, we estimated the impact of this emergent disease on the survival of avian populations. We find that populations were negatively affected by WNV in 23 of the 49 species studied (47%). We distinguished two groups of species: those for which WNV negatively impacted survival only during initial spread of the disease (n = 11), and those that show no signs of recovery since disease introduction (n = 12). Results provide a novel example of the taxonomic breadth and persistent impacts of this wildlife disease on a continental scale. Phylogenetic analyses further identify groups (New World sparrows, finches, and vireos) disproportionally affected by temporary or persistent WNV effects, suggesting an evolutionary dimension of disease risk. Identifying the factors affecting the persistence of a disease across host species is critical to mitigating its effects, particularly in a world marked by rapid anthropogenic change.The emergence of wildlife diseases in new geographic locations and naïve host populations is the inevitable consequence of a present-day global ecology characterized by unprecedented connectivity. Increases in anthropogenic stressors to the environment, including changes in land use and climate, have made exposure to new diseases more likely (1–3), and a rise in global transport and intercontinental travel has allowed “old” diseases to infect hosts in new environments (4–6). Such introductions may have negative effects on hosts that have never been exposed to a disease (7, 8), and once exposed, the resilience and recovery rates of naïve host populations remain unclear. Although such introductions are most often relegated to isolated regions, such as islands, the devastating impacts of emerging infectious diseases can also reach continental scales.The rapid spread of West Nile virus (WNV) across North America in just 5 y (1999–2003) has been associated with the death of millions of native wild birds that act as primary hosts to the virus (9). Despite the documented loss of individual birds and apparent impacts on bird populations, no study to date has fully documented the demographic impacts of WNV on avian populations across large regions of North America. Previous analyses identified the negative effects of WNV in roughly one-fifth to one-third of the bird species studied (8, 10). However, these studies used animal count data that likely underestimate impacts because, even in the face of high mortality, recruitment and immigration may mask population declines (11). WNV is hypothesized to influence bird populations through reductions in survival, which can be influenced by various biotic and abiotic factors, including age (12), climate (13, 14), and regional environment heterogeneity (15). In addition, a number of studies suggest that the impact of WNV on bird populations increases with human land use (16, 17). Understanding the contribution of disease to annual variation in survival across space and time requires rigorous demographic analyses that take into account these factors.We use 16 y of mark-recapture data collected at over 500 bird-banding stations across the United States (Fig. S1), in combination with newly developed spatiotemporal models of WNV risk (18) and land-use patterns, to examine the effects of WNV spread on survival rates of all bird species for which analyses were possible (49 species) (

Tmax: An Unconfounded Metric for Rate of Absorption in Single Dose Bioequivalence Studies

Purpose. While peak drug concentration (Cmax) is recognized to be contaminated by the extent of absorption, it has long served as the indicator of change in absorption rate in bioequivalence studies. This concentration measure per se is a measure of extreme drug exposure, not absorption rate. This paper redirects attention to Tmax as the absorption rate variable. Methods. We show that the time to peak measure (Tmax), if obtained from equally spaced sampling times during the suspected absorption phase, defines a count process which encapsulates the rate of absorption. Furthermore such count data appear to follow the single parameter Poisson distribution which characterizes the rate of many a discrete process, and which therefore supplies the proper theoretical basis to compare two or more formulations for differences in the rate of absorption. This paper urges limiting the use of peak height measures based on Cmax to evaluate only for dose-dumping, a legitimate safety concern with, any formulation. These principles and techniques are illustrated by a bioequivalence study in which two test suspensions are compared to a reference formulation. Results. Appropriate statistical evaluation of absorption rate via Tmax supports bioequivalence, whereas the customary analysis with Cmax leads to rejection of bioequivalence. This suggests that the inappropriate use of Cmax as a surrogate metric for absorption rate contributes to the unpredictable and uncertain outcome in bioequivalence evaluation today.     

Generic propoxyphene: need for clinical bioavailability evaluation

Plasma level data on two investigational capsule formulations of propoxyphene with similar physicochemical parameters demonstrate that the formulations have different in vivo bioavailabilities. The potential bioavailability problems with water-soluble drugs and the lack of correlation of in vitro and in vivo parameters for equivalent drug formulations are discussed.