Absorption rate assessment

Often, absorption occurs by multiple routes in humans. Dean et al. (1984) reported deaths and toxic effects as well as lowered blood cholinesterase levels and excretion of urinary 4-nitrophenol in several children who were exposed by inhalation, oral, and possibly dermal routes after the spraying of methyl parathion in a house. In the same incident (Dean et al. 1984), absorption was indicated in adults who also excreted 4-nitrophenol in the urine, though at lower levels than some of the children, and in the absence of other evidence of methyl parathion exposure. In this study, the potential for age-related differences in absorption rates could not be assessed because exposure levels were not known and the children may have been more highly exposed than the adults. Health effects from multiple routes are discussed in detail in Section 3.2. 

While in vivo studies assess absorption rates as process-lumped time constants from blood level versus time data, these rate parameters encompass the kinetics of dosage-form release, GI transit, metabolism, and membrane permeation. The use of isolated tissue and cellular preparations to screen for drug absorption potential and to evaluate absorption rate limits at the tissue and cellular levels has been expanded by the pharmaceutical industry over the past several years. For more detail in this regard, the reader is referred to an article by Stewart et al. [68] for references on these preparations and for additional details on the various experimental techniques outlined below. 

Some idea of the rate of absorption can be obtained from examination of the plasma concentration-time profile. It should be remembered, however, that the time to maximum plasma concentration Y ) is not when absorption is complete but when the rates of drug absorption and elimination are equal. Thus two drugs with the same absorption rate will differ in /max if elimination rates differ. Assessment of the rate of absorption can also be confounded by complex or slow drug distribution. For example, the calcium-channel blocker amlodipine has a much later /max than other similar drugs. This is not due to slow absorption but to partitioning in the liver membrane with slow redistribution. A quantitative assessment of the rate of absorption can be obtained by deconvolution of plasma profiles following IV and oral administration. 

Diltiazem Functional relationship between PK and PD parameters is described by hysteresis loops with a clockwise rotation. This cannot be explained in the classical way by the time lag between central and effect compartments. The model of down regulation/toler-ance development is proposed as a result supported by the finding that the shape of the hysteresis is dependent on the absorption rate of diltiazem, calculated as mean input time. Acute tolerance to dilitazem develops at least with the electrophysiologi-cal action of diltiazem after oral application and that the extent of tolerance development increases when decreasing its absorption rate. Bioequivalence assessment of diltiazem is possible using PD parameters however, because PK/PD relationships are influenced by the absorption rate, extent parameters may be misinterpreted when rate parameters of the test formulations are different... 

Intestinal absorption studies of Mn-MP were undertaken in an effort to assess the viability of the metalloporphyrin as an oral hepatobiliary agent [101, 102]. Mixed micelles of Mn-MP complexed with monoolein and taurocholate were administered to rats, resulting in liver image enhancement 68% above baseline levels six hours after administration [101]. In pigs, the mixed micelle preparation showed variable enhancement over 24 hours. Observation that Mn-MP interacts with oleic acid vesicles [103] led to investigations of the effect of oleic acid on the absorption rate of Mn-MP from the small bowel into the circulatory system [102,104]. The increase in absorption of the complex was mediated by a decrease in the relaxivity of the metalloporphyrin resulting from the interaction with the lipid vesicles. 

Pharmacokinetic Measures of Systemic Exposure Both direct (e.g., rate constant, rate profile) and indirect (e.g., Cmax, Tmax, mean absorption time, mean residence time, Cmax normalized to AUC) pharmacokinetic measures are limited in their ability to assess rate of absorption. This guidance, therefore, recommends a change in focus from these direct or indirect measures of absorption rate to measures of systemic exposure. Cmax and AUC can continue to be used as measures for product quality BA and BE, but more in terms of their capacity to assess exposure than their capacity to reflect rate and extent of absorption. Reliance on systemic exposure measures should reflect comparable rate and extent of absorption, which in turn should achieve the underlying statutory and regulatory objective of ensuring comparable therapeutic effects. Exposure measures are defined relative to early, peak, and total portions of the plasma, serum, or blood concentration-time profile, as follows ... 

In vivo skin absorption studies for risk assessment purposes are most often performed on laboratory rats. While the USEPA (1998) states that the rat is the only acceptable species, the OECD (2004b) mentions that also other animal species can be used when they have been proven to have more similar skin absorption rates to human. An advantage of the rat is that this is the species used in most toxicological and kinetic studies. On the other hand, it is known that data from rat studies generally overestimate human skin absorption (ECETOC, 1993 van de Sandt et al, 2000). As indicated before, and to the best of our knowledge, no extensive validation of the rat in vivo study has been performed in which reproducibility and the relationship to human skin absorption have been established. 

Radiation model involving multi-lamp reactors is provided by Yokota and Suzuki (22). Based on a diffused line source emission model, the light absorption rate in any geometrical photoreactor with multiple lamps was assessed, and the work reveals the existence of optimum light arrangement. 

As mentioned above, interindividual differences in absorption rate can be explained by SNPs in membrane transporters. However, SNPs in other genes, which are involved in the regulation of transporter genes, could also contribute to interindividual differences. Therefore, the exploitation of array data will be very important to assess the influence of the various genotypes in drug absorption. 

Macheras P, Symillides M, Reppas C. An improved intercept method for the assessment of absorption rate in bioequivalence studies. Pharm Res 1996 13 1753-1756. 

Risk assessment. This model successfully described the differences in disposition of 2-butoxy-ethanol, based on urinary profdes of metabolites, in various exposure routes by taking into account the differences in absorption rate and by incorporating a minor pathway for metabolism (glucuronidation) by skin (Shyr et al. 1993). The model was reasonably successful in predicting the experimental rat data produced by Johanson et al. (1986a). The value of the model lies in the ability to extrapolate to the human situation from the routes of exposure likely to be used in experimental assays. 

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