Vertical allometry: fact or fiction?

In pharmacokinetics, vertical allometry is referred to the clearance of a drug when the predicted human clearance is substantially higher than the observed human clearance. Vertical allometry was initially reported for diazepam based on a 33-fold higher human predicted clearance than the observed human clearance. In recent years, it has been found that many other drugs besides diazepam, can be classified as drugs which exhibit vertical allometry.

The bioavailability of intranasal and smoked methamphetamine.

Background: Patients in harm-reduction treatment programs are switching from intravenous to other routes of methamphetamine (INN, metamfetamine) administration to avoid risks associated with needle use. Relatively little has been reported about the bioavailability of methamphetamine when smoked or used intranasally.

Methods: Eight experienced methamphetamine users were administered smoked or intranasal methamphetamine concurrently with an intravenous dose of deuterium-labeled methamphetamine.

Pharmacokinetics of doxorubicin administered i.v. as Myocet (TLC D-99; liposome-encapsulated doxorubicin citrate) compared with conventional doxorubicin when given in combination with cyclophosphamide in patients with metastatic breast cancer.

Myocet (TLC D-99) is a liposomal formulation of the anti-neoplastic drug doxorubicin with an improved therapeutic index compared with conventional doxorubicin. The objective of this study was to assess the plasma disposition of doxorubicin when administered i.v.

Human in vivo competitive inhibition of P450 substrates: increased plasma concentrations as a function of hepatic extraction ratio and percent inhibition.

The purpose of this note is to posit and discuss the concept of "competitive inhibition potential" (CIP), which is an in vivo index of the ability of a competitive inhibitor to elevate plasma concentrations of drug substrates, when the competitive inhibitor is administered at its usual and customary dose.

Cytochrome P450 3A4 in vivo ketoconazole competitive inhibition: determination of Ki and dangers associated with high clearance drugs in general.

Assuming complete hepatic substrate metabolism and system linearity, quantitative effects of in vivo competitive inhibition are investigated. Following oral administration of a substrate in the presence of a competitive inhibitor, determination of the inhibition constant (Ki) is possible when plasma concentration-time profiles of both substrate and inhibitor are available. When triazolam is the P450 3A4 substrate and ketoconazole the competitive inhibitor, Ki approximately 1.

Estimation of Ki in a competitive enzyme-inhibition model: comparisons among three methods of data analysis.

There are a variety of methods available to calculate the inhibition constant (Ki) that characterizes substrate inhibition by a competitive inhibitor. Linearized versions of the Michaelis-Menten equation (e.g.

First-time-in-human dose selection: allometric thoughts and perspectives.

Some of the many factors that influence dose selection in first-time-in-human studies are examined. These include animal toxicology, toxicokinetics, allometric scaling, pharmacokinetics, body surface area correlations, and integration of preclinical pharmacologic and toxicologic data. Appropriate preclinical evaluation and analysis may reduce the frequency and severity of unexpected toxic events arising during single-dose, phase I testing.

Human dolasetron pharmacokinetics: II. Absorption and disposition following single-dose oral administration to normal male subjects.

Dolasetron is a 5-hydroxytryptamine antagonist active at type III receptors; it is presently undergoing clinical evaluation for the reduction/prevention of cancer chemotherapy-induced nausea and vomiting. A previous study demonstrated that following intravenous administration to healthy male subjects, dolasetron disappeared extremely rapidly from plasma, and less than 1 per cent of the dose appeared in the urine. A major plasma metabolite, reduced dolasetron, peaked rapidly in the plasma.

Human dolasetron pharmacokinetics: I. Disposition following single-dose intravenous administration to normal male subjects.

Dolasetron is a 5-hydroxytryptamine antagonist active at type III receptors; it is presently undergoing clinical evaluation for the reduction/prevention of cancer chemotherapy-induced nausea and vomiting. Following intravenous administration to healthy male subjects of doses ranging from 0.6 to 5 mg kg-1, dolasetron disappeared extremely rapidly from plasma; concentrations were generally measurable for only 2-4 h.

Pharmacokinetics: philosophy of modeling.

Generally speaking, there are two extremes of scientific personality types: sharpeners and levelers. Sharpeners, highly attuned to system differences and nuances, and always alert to distinctions, try hard to let nothing slip by them unnoticed. Levelers, on the other hand, attempt to submerge system differences, reveal uniform patterns, and condense disparate elements.

Gompertz mortality analysis: aging, longevity hormesis and toxicity.

The hazard function, denoted h(x), is the probability of death during an interval of time [Formula: see text], assuming survival to the beginning of the interval. Brues and Sacher provided both theoretical and experimental support for the assumption that h(x) is an exponential function of the mean intensity of physiologic injury for a homogeneous mammalian population provided an adequate diet, kept free of preventable disease and maintained under favorable, uniform conditions. Consequently, the Napierian logarithm of the hazard function, the 'Gompertzian', is proportional to the mean intensity of physiologic injury under the aforementioned conditions.

Scientific creativity: a review.

Aside from possession of the relevant knowledge, skills, and intelligence, what seems to characterize the creative scientist is his imagination, originality, and ingenuity in combining existing knowledge into a new and unified scheme. This creativity frequently emerges from an aesthetic, poetic sense of freedom derived from work, an uninhibited playful activity of exploring a medium for its own sake. We speculate thus: With a preference for irregularities and disorder, the creative scientist temporarily takes leave of his senses, permitting expression of unconfigurated forces of his irrational unconscious.

Biphasic mortality response of chipmunks in the wild to single doses of ionizing radiation: toxicity and longevity hormesis.

Based on survivalship data from Tryon and Snyder, wild chipmunks (Tamias striatus), captured, exposed to single doses of either 200 or 400 rad ionizing radiation, and subsequently returned to their natural habitat, exhibited a biphasic response in age-specific mortality rate (omega x). On the one hand, a residuum of unrepaired toxicity (injury) appeared to persist and manifest itself throughout life (enhancement of omega x values). A second response, termed longevity hormesis (of unknown mechanism), was also observed.

Gompertzian mortality derived from competition between cell-types: congenital, toxicologic and biometric determinants of longevity.

Gompertz-Makeham kinetics of population mortality is derived in terms of competition between hypothetical life-prolonging and life-shortening regulatory elements (cells) interacting in each organism by generalized Volterra-type competitive exclusion. The model is developed on two levels, the first applicable to homogeneous populations, and the second, a statistical generalization, applicable to inhomogeneous populations. It offers a natural classification of effects of exogeneous agents on longevity, including hormetic and paradoxical effects of toxic substances, thus relating to problems of risk assessment by extrapolation from high to low doses.

A Gompertz age-specific mortality rate model of aging: modification by dietary restriction in rats.

A Gompertz age-specific mortality rate model characterizing actuarial effects of food restriction in rats was developed based on mortality data from the study of Yu et al. (J. Gerontol.

Human serum and plasma protein binding of enoximone and its sulfoxide metabolite.

Experimental factors and determinants of the protein binding of enoximone (a new cardiotonic agent) were investigated in human serum from healthy, drug-free subjects using a rapid ultrafiltration method; these factors and determinants included nonspecific binding to the apparatus, ultrafiltrate volume, temperature, serum pH, enoximone serum concentration, and enoximone sulfoxide (metabolite) concentration. It was demonstrated from mass balance experiments that nonspecific binding to the apparatus did not occur. Within the range investigated, ultrafiltrate volume did not affect the binding result.

Desmethyldiazepam pharmacokinetics: studies following intravenous and oral desmethyldiazepam, oral clorazepate, and intravenous diazepam.

After single 10-mg intravenous (IV) doses of desmethyldiazepam (DMDZ) to 12 healthy human volunteers, (mean age, 62 years) blood samples were obtained over the next 14 or more days. Mean kinetic variables were volume of distribution (Vd), 90 liters; elimination half-life (t1/2), 93 hours; and clearance, 12.3 mL/min.