Microelectrometric titration measurement of the pKa's and partition and drug distribution coefficients of narcotics and narcotic antagonists and their pH and temperature dependence

Abstract

The pKa's, partition coefficients, and drug distribution coefficients (apparent partition coefficients) have been investigated for a number of narcotics and, where possible, for their congener narcotic antagonists. These studies were carried out by a microelectrometric titration technique as a function of temperature and pH. This method enables one to determine not only the dissociation constants to deconvolute overlapping pKa's, but also to determine the solubilities of oil-water distribution of these various drugs. The drug distribution coefficients displayed marked sensitivity to pH at values which span the range of attainable human physiological pH values. This has significant pharmacological implications for proper choice and scaling of drug dosages under various clinical situations. The partition coefficients and drug distribution coefficients were noticeably different at 20 degrees (where such measurements are customarily made) than at 37 degrees (body temperature). Furthermore, various drugs exhibit very nonequivalent increases in drug distribution coefficients with increasing temperature, ranginf from 21% for morephine to 200% for naltrexone. This nonregularity indicates that it will not be valid to extrapolate by any constant factor the measurements made at lower temperatures. Even the true partition coefficients increase with temperature from 20 degrees to 37 degrees. There is more of a difference in the drug distribution coefficients for naloxone and naltrexone than might have been expected from the similarities in their structures with naltrexone being significantly less lipophilic than naloxone. This would imply that this would lead to naloxone having a more rapid onset for antagonist activity and likewise a shorter duration of action than naltrexone.

Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter

“…An initial PBPK model was developed using morphine‐specific physicochemical parameters and in vitro and in vivo data, as summarized in Table 1 4, 5, 6, 14, 15, 16, 17, 18. Morphine was assumed to be transported into hepatocytes via passive diffusion and OCT1 transporter‐mediated uptake.…”

“…Morphine is known to be water‐soluble with low lipophilicity (log P = 0.77; Table 1, 4, 5, 6, 14, 15, 16, 17, 18) and this will make it more difficult for the drug to pass through the membrane phospholipid bilayer; in agreement with this morphine has shown poor passive membrane permeability in HEK293 cells 6. We previously identified the PG contribution of OCT1, an uptake transporter at the sinusoidal membrane of human hepatocytes, to morphine CL in pediatric patients after intravenous administration.…”

“…In this study, the relevant physicochemical parameters, in vitro , and in vivo data of morphine were collected from the literature. The morphine‐specific data collected are summarized in Table 1 4, 5, 6, 14, 15, 16, 17, 18. The morphine compound file was developed and validated in the adult Simcyp Simulator model (consisting of adult systems parameters) before being used in the Pediatric Simcyp Simulator model, which considers age‐dependent anatomic and physiological changes.…”

“…The maximum uptake rate for morphine transport in hepatocytes (J max , pmol/min/million hepatocytes) estimates, for each OCT1 genotype, was defined as the mean of J max ' (pmol/min/mg lysate protein) of the OCT1 variants in the OCT1‐overexpression cell system, as shown in Table 1 4, 5, 6, 14, 15, 16, 17, 18. For example, the J max ' estimate for OCT1*1/*2 was calculated as the mean of J max ' of *1 variant (29 pmol/min/mg lysate protein) and J max *2 variant (7.21 pmol/min/mg lysate protein); (29.0 + 7.21)/2 = 18.1 pmol/min/mg lysate protein, as summarized in Table 2 6.…”

“…A comprehensive PG study found that diplotypes containing haplotype #4 in UGT2B7 resulted in a significant increase in the formation of morphine 3 and 6‐glucuronidation (45% and 56%, respectively) compared with diplotypes without the haplotype #4 34. Based on the observed activity changes as a result of UGT2B7 genetic variants, the maximum velocity of UGT2B7‐mediated morphine glucuronidation in human liver microsomes was scaled from 50–150% of the default value (set at 100%), as shown in Table 1, 4, 5, 6, 14, 15, 16, 17, 18 for the simulations in virtual pediatric and adult healthy subjects.…”