Journal of Pharmacokinetics and Biopharmaceutics

Theoretical expressions are derived to predict the amount of a drug reaching the dermal capillaries as a function of simple physicochemical parameters. The mathematical approach involves the solution of the diffusion equation for the drug in the skin using the technique of Laplace transformation. Firstorder kinetics are assumed for the absorption of drug from the vehicle into the skin and for uptake into the capillaries. The relative importance of these different processes (absorption from vehicle, diffusion through the skin, and capillary removal) involved in the percutaneous penetration of a drug is discussed, and their influence upon the time course of the absorption phenomenon is illustrated.

We describe a method of rapidly obtaining a specified steady state plasma concentration of an intravenous drug within precise limits. The technique requires an initial bolus to raise the plasma concentration to the upper limit followed by a series of constant-rate infusions each of which is associated with a minimum plasma concentration equal to the tower limit. The infusion rate is stepped down when the plasma concentration returns to the upper limit. Computer simulation, based on the method, is used to generate plasma concentration–time curves with fluctuations of up to 10% about selected steady state concentrations of amrinone, esmolol, lidocaine, midazolam, propofol, and theophylline. The utility of this general approach to intravenous dosing and potential limitations of the method are discussed.

The conventional convection-dispersion (also called axial dispersion) model is widely used to interrelate hepatic availability (F) and clearance (Cl) with the morphology and physiology of the liver and to predict effects such as changes in liver blood flow on F and Cl. An extended form of the convection-dispersion model has been developed to adequately describe the outflow concentration–time profiles for vascular markers at both short and long times after bolus injections into perfused livers. The model, based on flux concentration and a convolution of catheters and large vessels, assumes that solute elimination in hepatocytes follows either fast distribution into or radial diffusion in hepatocytes. The model includes a secondary vascular compartment, postulated to be interconnecting sinusoids. Analysis of the mean hepatic transit time (MTT) and normalized variance (CV2) of solutes with extraction showed that the discrepancy between the predictions of MTT and CV2 for the extended and unweighted conventional convection-dispersion models decreases as hepatic extraction increases. A correspondence of more than 95% in F and Cl exists for all solute extractions. In addition, the analysis showed that the outflow concentration–time profiles for both the extended and conventional models are essentially identical irrespective of the magnitude of rate constants representing permeability, volume, and clearance parameters, providing that there is significant hepatic extraction. In conclusion, the application of a newly developed extended convection-dispersion model has shown that the unweighted conventional convection-dispersion model can be used to describe the disposition of extracted solutes and, in particular, to estimate hepatic availability and clearance in both experimental and clinical situations.

The pharmacokinetics of recombinant hirudin (rec-hirudin, Ciba-Geigy, CGP 39 393) in healthy volunteers after iv administration was investigated on the basis of the data from five different studies. A total of 77 plasma profiles following a single iv bolus dose of either 0.1, 0.3, 0.5, or 1 mg/kg of rec-hirudin was used for the evaulation. Plasma concentrations and especially AUC were proportional to the dose. Kinetics of rec-hirudin after a bolus iv injection were best described by a three-compartment open model. Mean apparent terminal half-life was 2.8 hr and the total clearance 0.138 L/hr per kg.

Terminal half-lives, percent excreted unchanged, and reported changes in half-life associated with decreased renal and hepatic functions are tabulated for 186 drugs studied in humans. References from 332 original articles are keyed to each pharmacokinetic value. When given in the original article, range of values found and number of subjects studied are listed with each value. All references were critically evaluated by the authors before values were included in the tabulation.

The purpose of this investigation was to study, by digital computer simulation, the accumulation kinetics of drugs which exhibit concentration-dependent binding to tissues and either linear (constant free fraction) or concentration-dependent (increasing free fraction with increasing drug concentration) binding to plasma proteins. It was assumed that elimination rate is proportional to free drug concentration in plasma and that there occurs instantaneous equilibration of drug between vascular and nonvascular spaces. Nonlinear binding can yield, under certain conditions, apparently biexponential plasma concentrationtime curves which may be misinterpreted as being representative of a linear and biexponential-system. Such misinterpretation would cause the following errors in the prediction of drug accumulation and elimination kinetics during and after constantrate infusion: (a) the time required to reach steady state may be overestimated, and (b) the prominence of the apparent distribution phase after cessation of infusion may be underestimated. Drugs with linear and nonlinear plasma protein binding characteristics differ with respect to the relationship between infusion rate and steadystate concentration. This relationship is linear when plasma protein binding is linear. Steadystate concentration increases less than proportionally with increasing infusion rate if plasma protein binding is drug concentration dependent.

The influence of enzymic distribution on lidocaine metabolism was investigated in the once-through perfused rat liver preparation. Low input concentrations of14C-lidocaine (1–2 μM) and preformed monoethylglycine xylidide (MEGX; 2.3–2.8 μM) were delivered by normal and retrograde flow directions to the liver preparations at 10 ml/min per liver. Upon reversal of normal to retrograde delivery of lidocaine, the rates at which lidocaine, MEGX, and glycine xylidide (GX) left the liver almost doubled, whereas the rates of appearance of (total) hydroxylated lidocaine and MEGX in bile and perfusate increased to lesser extents. Upon reversal of normal to retrograde delivery of preformed MEGX, the rates of appearance of MEGX and GX were virtually unchanged. Computer simulations on lidocaine and preformed MEGX metabolism were performed on both evenly distributed (“parallel tube” model) and enzyme-distributed systems. An even or parallel distribution of N-deethylation and hydroxylation activities for lidocaine metabolism failed to predict the observed increased hepatic availability of lidocaine. Rather, the distribution of a low-affinity, high-capacity N-deethylation system anterior to a high-affinity, lowcapacity hydroxylation system for lidocaine metabolism adequately predicted the increased hepatic availability of lidocaine. Further extension of these consistent enzyme-distributed models on the metabolism of lidocaine metabolites suggests that the N-deethylation and hydroxylation activities for the metabolism of lidocaine, MEGX, 3-hydroxyidocaine, and 3-hydroxy MEGX are not identically distributed. When these enzymedistributed models were appraised with reference to the “parallel tube” and “wellstirred” models of hepatic drug clearance, predictions from these.enzymedistributed models proved to be superior to the “parallel tube” and “well-stirred” models for the present data on lidocaine metabolites with normal and retrograde perfusions. Previously published data on lidocaine and MEGX metabolism after inputting 4 μg/ml (17 μM) lidocaine at flow rates of 10, 12, 14, and 16 ml/min were reexamined with respect to the adequacy of these enzyme-distributed models. They were found to be superior to the evenly-distributed or “parallel tube” model in predicting hepatic availability of lidocaine and the rate of appearance of MEGX. However, the enzyme-distributed systems were not as consistent as the “well-stirred” model in predicting lidocaine hepatic availability in these flow experiments.

Huntet al. introduced the concept of the Drug Targeting Index (DTI) to quantify the gain associated with regional drug administration and targeting and showed that for the ideal case of all drug first reaching the targetDTI=1+CL s/(Q T(1−E T)) whereCL s is the total clearance of drug from the body (including the target tissue),Q T is the target blood flow andE T is the steady-state extraction ratio of the drug in the target. In the model they portrayed the tissue as a homogeneous organ. A more general pharmacokinetic model has been developed that takes into account the three anatomical spaces (vascular, interstitial, and intracellular) of the target organ or tissue and that, in addition to unbound drug permeating the vascular and cellular membranes, protein-bound drug can also flux between the vascular and interstitial spaces. Elimination of unbound drug can take place from the cellular and interstitial spaces. An important parameter influencing theDTI is shown to be the fraction of targeted dose that is eliminated there before it reaches the systemic circulation,f T. Equations have been developed showing the relationship betweenf T andE T and forDTI when drug is administered at the various sites within the tissue and under a variety of conditions. Only when drug is administered into the target arterial blood stream or when distribution of drug within the target tissue is perfusion rate-limited, doesf T=E T andDTI=1+CL s/(Q T·(1−E T)). Otherwise consideration needs to be given to the permeabilities of both the unbound and bound drug and site of target administration, interstitial or intracellular. Thenf T is greater thanE T andDTI is greater than that expected had perfusion-rate limited distribution prevailed. The maximum benefit inDTI is seen for a drug of low cellular permeability but high cellular intrinsic clearance administered intracellularly.