Purpose. To develop a simple approach for investigating absorption kinetics, which does not require modeling assumptions or intravenous data. Methods. The concentration (C) -time (t) data are plotted as a phase plane plot (dC/dt versus C). Errorless C,t data were generated from one and two compartment models employing first-order, zero-order and Michaelis-Menten input kinetics, and the phase plane plots were constructed. A simple test based on the ratio of slopes of the separate linear regression analyses of absorption and elimination data of the phase plane plot is proposed to justify or not the presence of zero-order input kinetics. Errant data were used to assess the performance of the test developed. Literature data of theophylline and nitroglycerin formulations were analyzed using the phase plane plot. Input rate-time profiles were constructed for one compartment model drugs utilizing the data of the phase plane plot. Results. The geometric forms of the phase plane plots derived from the errorless data of the various pharmacokinetic models were found to be indicative of the absorption kinetics. Very good results were obtained when the test for the discernment of absorption kinetics was applied to errant data. Zero-order absorption kinetics were justified (i) for the transdermal absorption of nitroglycerin and (ii) only for a certain period of time, for the gastrointestinal absorption of theophylline. Conclusions. Investigation of absorption kinetics can be accomplished with the phase plane method. The cumulative character of the classical percent absorbed versus time plots can be misleading in justifying the presence of zero-order input kinetics.

The objectives of these studies were, first, to determine the effect of elevated luminal viscosity on the gastrointestinal absorption of four model drugs and, second, to identify the key processes influencing drug absorption under elevated viscosity conditions. Studies were conducted in vitro and in healthy female mongrel does under fasting conditions. In the canine model, both the rate and extent of paracetamol and hydrochlorothiazide absorption were significantly decreased by the coadministration of 15 g guar gum dissolved in 500 ml normal saline. In the case of cimetidine, the rate but not extent of absorption was decreased. Owing to the high variability in the data, no statistically based conclusion could be drawn about the effects of coadministered guar gum on the oral absorption of the poorly soluble mefenamic acid. Based on the in vitro data, it appears that substantial reductions in the dissolution rate of paracetamol, hydrochlorothiazide and cimetidine account for the effects observed in vivo. It is concluded that the effect of an elevation in the intraluminal viscosity on drug absorption is greatest for highly soluble drugs, and results from a combination of a decrease in dissolution rate and gastric emptying rate. (C) 1998 Elsevier Science B.V.

The objective of this study was to evaluate the effects which hydroxypropylmethylcellulose (HPMC) may exert on oral drug absorption, in cases where this soluble fiber is administered to regulate blood lipid levels. Studies were conducted in vitro and in healthy female mongrel dogs using two different grades of HPMC, i.e. K8515 HPMC and ultra high molecular weight (UHMW) HPMC. The maximum plasma concentration, C-max, of paracetamol and both the C-max and the area under the concentration-time curve, AUC, of cimetidine were significantly decreased by the coadministration of 10 g of K8515 HPMC or 7.5 g of UHMW HPMC dissolved in 500 mL normal saline under fasting conditions. No statistically significant effects were observed on hydrochlorothiazide or mefenamic acid absorption. Based on in vitro data and previous studies it appears that reductions in gastric emptying and dissolution rate of paracetamol account for the effect observed in vivo. For cimetidine, a drug which can be absorbed from both the small and the large intestine, the indigestibility of HPMC in the colon in addition to the great reduction of dissolution rate led to reductions of both the C-max and AUC values. The long T-max values, even in the absence of HPMCs and the more modest reduction of the dissolution rate of hydrochlorothiazide by the HPMCs are thought to have precluded the observation of any significant alterations in the in vivo absorption profile. Owing to its erratic absorption, no statistically based conclusion could be drawn about the effects of coadministered HPMC on the oral absorption of the poorly soluble mefenamic acid. It is concluded that the effects of HPMCs on drug absorption in dogs are most pronounced for compounds with absorption profiles that are dependent on gastric emptying, i.e. compounds that are highly water soluble and that exhibit short T-max values. Compounds with long absorption profiles appear to be less susceptible to changes in absorption behavior due to coadministration of HPMCs. (C) 1998 John Wiley & Sons, Ltd.