Tommy B. Andersson

Pharmacokinetics, metabolism and interactions of acid pump inhibitors : Focus on omeprazole, lansoprazole and pantoprazole

SummaryThis review updates and evaluates the currently available information regarding the pharmacokinetics, metabolism and interactions of the acid pump inhibitors omeprazole, lansoprazole and pantoprazole. Differences and similarities between the compounds are discussed.Omeprazole, lansoprazole and pantoprazole are all mainly metabolised by the polymorphically expressed cytochrome P450 (CYP) isoform S-mephenytoin hydroxylase (CYP2C19), which means that within a population a few individuals (3% of Caucasians) metabolise the compounds slowly compared with the majority of the population. For all 3 compounds, the area under the plasma concentration-versus-time curve (AUC) for a slow metaboliser is, in general, approximately 5 times higher than that in an average patient. Since all 3 compounds are considered safe and well tolerated, and no dosage-related adverse drug reactions have been identified, this finding seems to be of no clinical relevance.The acid pump inhibitors seem to be similarly handled in the elderly, where a somewhat slower elimination can be demonstrated compared with young individuals. In patients with renal insufficiency, omeprazole is eliminated as in healthy individuals, whereas the data on lansoprazole and pantoprazole are unresolved. In patients with hepatic insufficiency, as expected, the elimination rates of all 3 compounds are substantially decreased.No clinically relevant effects on specific endogenous glandular functions, such as the adrenal (cortisol), the gonads or the thyroid, were demonstrated for omeprazole and pantoprazole, whereas a few minor concerns have been raised regarding lansoprazole.The absorption of some compounds, e.g. digoxin, might be altered as a result of the increased gastric pH obtained during treatment with acid pump inhibitors, and, accordingly, similar effects are expected irrespective of which acid pump inhibitor is given.The effect of the acid pump inhibitors on enzymes in the liver has been intensely debated, and some authors have claimed that lansoprazole and pantoprazole have less potential than omeprazole to interact with other drugs metabolised by CYP. However, after assessment of available data in this area, the conclusion is that all 3 acid pump inhibitors have a very limited potential for drug interactions at the CYP level. In addition, the small effects on CYP reported for these compounds are rarely of any clinical relevance, considering the normal intra- (and inter-)individual variations in metabolism observed for most drugs.In conclusion, omeprazole, lansoprazole and pantoprazole are structurally very similar, and an evaluation of available data indicates that also with respect to pharmacokinetics, metabolism and interactions in general they demonstrate very similar properties, even though omeprazole has been more thoroughly studied with regard to different effects.

Hepatocyte-like cells derived from human embryonic stem cells specifically via definitive endoderm and a progenitor stage

Human embryonic stem cells offer a potential unlimited supply for functional hepatocytes, since they can differentiate into hepatocyte-like cells displaying a characteristic hepatic morphology and expressing various hepatic markers. These cells could be used in various applications such as studies of drug metabolism and hepatotoxicity, which however, would require a significant expression of drug metabolizing enzymes. To derive these cells we use a stepwise differentiation protocol where growth- and maturation factors are added. The first phase involves the formation of definitive endoderm. Next, these cells are treated with factors known to promote the induction and proliferation towards hepatic progenitor cell types. In the last phase the cells are terminally differentiated and maturated into functional hepatocyte-like cells. The cultures were characterized by analysis of endodermal or hepatic markers and compared to cultures derived without induction via definitive endoderm. Hepatic functions such as urea secretion, glycogen storage, indocyanine green uptake and secretion, and cytochrome P450-expression and activity were evaluated. The DE-Hep showed a hepatocyte morphology with sub-organized cells and exhibited many liver-functions including transporter activity and capacity to metabolize drugs specific for important cytochrome P450 sub-families. This represents an important step in differentiation of hESC into functional hepatocytes.

Effects of food deprivation and handling stress on head kidney 17α-hydroxyprogesterone 21-hydroxylase activity, plasma cortisol and the activities of liver detoxification enzymes in rainbow trout

The 21-hydroxylation of 17alpha-hydroxyprogesterone is one step in the biosynthesis of corticosteroids. Both 7 days of handling-induced stress and 7 weeks of food deprivation significantly elevated head kidney microsomal 17alpha-hydroxyprogesterone 21-hydroxylase activity in juvenile rainbow trout. The increased 21-hydroxylase activity was not paralleled by changes in plasma cortisol levels induced by handling stress whereas food deprivation for 3 and 7 weeks increased both 21-hydroxylase activity and plasma cortisol levels significantly. Food deprivation in rainbow trout affected detoxification enzyme activities, namely glutathione-S-transferase (GST), uridine-di-phosphate glucuronosyltransferase (UGT) and glutathione reductase (GR) activities in the liver. Together our observations suggest that experimental conditions can affect experimental results, especially the values of parameters like GST, UGT and GR. Furthermore, alterations in the metabolic state of the liver caused by stress or food deprivation can alter the balance between detoxification enzymes in rainbow trout liver.

PhRMA White Paper on ADME Pharmacogenomics

Pharmacogenomic (PGx) research on the absorption, distribution, metabolism, and excretion (ADME) properties of drugs has begun to have impact for both drug development and utilization. To provide a cross‐industry perspective on the utility of ADME PGx, the Pharmaceutical Research and Manufacturers of America (PhRMA) conducted a survey of major pharmaceutical companies on their PGx practices and applications during 2003–2005. This white paper summarizes and interprets the results of the survey, highlights the contributions and applications of PGx by industrial scientists as reflected by original research publications, and discusses changes in drug labels that improve drug utilization by inclusion of PGx information. In addition, the paper includes a brief review on the clinically relevant genetic variants of drug‐metabolizing enzymes and transporters most relevant to the pharmaceutical industry.

Fish primary hepatocyte culture; an important model for xenobiotic metabolism and toxicity studies

Abstract The aquatic environment is affected by numerous chemical contaminants. There is an increasing need to identify these chemicals and evaluate their potential toxicity towards aquatic life. In this review, we present the technique of primary cell culture of fish hepatocytes as one adjunct model for the ecotoxicological evaluation of the potential hazards of xenobiotics in the aquatic environment. The isolation of hepatocytes involves the perfusion of the liver with a Ca 2+ -free balanced saline solution followed by a second perfusion with the digesting enzyme collagenase. Hepatocytes or parenchymal cells can be separated from cell debris and from non-parenchymal cells by low-speed centrifugation. Fish hepatocytes have been shown to retain many important functions in primary cell culture which is a prerequisite for obtaining results relevant to the in-vivo situation. Thus, fish primary hepatocytes have been used to study the metabolism of xenobotics, the formation of toxic products, chemical-induced DNA damage, the induction of enzymes, peroxisome proliferation, and effects on hormone-signalling systems, etc. From the results, the mechanisms involved in chemical-induced toxicity can be determined in more detail than would be possible in in-vivo studies.

Phenobarbital Induction of CYP1A1 Gene Expression in a Primary Culture of Rainbow Trout Hepatocytes

In mammals, phenobarbital (PB) is an in vivo inducer of the cytochrome P4502B (CYP2B) family, whereas in teleosts PB induction of cytochrome P450 is unclear. We show that teleost cytochrome P4502K1 (CYP2K1) protein levels and 7-pentoxyresorufin-O-deethylase activity were not induced by exposure of primary cultures of rainbow trout hepatocytes to PB. Instead, cytochrome P4501A1 (CYP1A1) gene expression was strongly induced by PB, based upon observations of marked increases in CYP1A1 mRNA, CYP1A1 protein, and 7-ethoxyresorufin-O-deethylase activity. In accordance with these data we provide a temporal study employing antibodies for the aromatic hydrocarbon (Ah) receptor that showed an increase in Ah receptor in nuclear extracts prepared from cells exposed to PB. Employment of the electrophoretic mobility shift assay (EMSA) showed PB to cause activation or “transformation” of the Ah receptor in nuclear extracts. Studies employing actinomycin D and cycloheximide indicated that PB induction of CYP1A1 was regulated at both the transcriptional and post-transcriptional levels. Nuclear run-off experiments confirm that PB causes an increase in CYP1A1 transcription. Inhibition of protein synthesis led to the superinduction of CYP1A1 mRNA, suggesting the regulation of teleost CYP1A1 may involve a labile repressor protein. These findings suggest that PB induction of the CYP1A1 gene involves the Ah receptor and is via transcriptional activation.

Pharmacokinetics of [14C]omeprazole in patients with liver cirrhosis

SummaryThe pharmacokinetics of omeprazole and its metabolites following single doses were studied in 8 patients with liver cirrhosis. Each patient participated in 2 experiments in which [14C]omeprazole was administered either intravenously (20mg) or in an oral solution (40mg) in a randomised crossover design. Plasma concentrations of omeprazole and 2 of its identified metabolites, as well as total radioactivity were followed for 24h; urinary excretion was followed for 96h.The mean elimination half-life of omeprazole in the patients with cirrhosis was 2.8h and the mean total plasma clearance was 67 ml/min (4.02 L/h); corresponding values from separate studies in young healthy volunteers were 0.7h and 594 ml/min (35.64 L/h). The mean systemic availability was nearly 100% in the patients with cirrhosis whereas the previously reported value in young volunteers was only 56%. Almost 80% of a given dose was excreted as urinary metabolites in both patients and young volunteers. It is concluded that, as the hepatic clearance of omeprazole was substantially reduced in these patients, the dose of omeprazole needed for a certain degree of acid suppression is lower in patients with liver cirrhosis.

The effect of chemical heterogeneity of HPMC on polymer release from matrix tablets.

Polymer release from hydrophilic matrix tablets, composed of hydroxypropyl methylcellulose, was studied for seven different polymer batches. A time difference of more than 80h between fully dissolved tablets was noticed although the batches were of the same pharmaceutical substituent (USP 2208) and viscosity (100 cps) grade. To find the functionality related parameters for polymer release from hydrophilic matrix tablets the polymer samples were characterised according to size and chemical composition. The size of the polymers was characterised by size-exclusion chromatography with multi-angle light scattering and refractive index detection. The average amount of substituents was measured with nuclear magnetic resonance and the distribution of the substituents along the cellulose chain was determined with high-performance anion-exchange chromatography with pulsed amperometric detection after acid and enzymatic hydrolysis. The results indicated that other types of interactions apart from entanglements were present between the polymer chains, which seemed to affect the polymer release. Most importantly, this study has shown a correlation between the polymer release and the substituent pattern, where the samples with slow release also were more heterogeneously substituted along the polymer chain. From this we can conclude that polymer release is very sensitive to alterations in chemical composition.

Omeprazole Disposition in Children following Single‐Dose Administration

Omeprazole is frequently used to treat gastroesophageal reflux in infants and children despite the lack of age‐specific pharmacokinetic and dosing information in the approved product labeling. To address this challenge, the authors examined the potential influence of development and cytochrome P450 2C19 (CYP2C19) genotype on omeprazole disposition by conducting two pharmacokinetic (PK) studies in children and adolescents (ages 2–16 years) after a single oral 10‐ or 20‐mg dose of the drug. Plasma omeprazole concentrations were determined by HPLC‐MS from seven plasma samples obtained over a 6‐hour postdose period. Pharmacokinetic parameters were determined by noncompartmental methods. Subjects were genotyped for CYP2C19 by PCR‐RFLP Data were available from 37 patients (19 female), 10 of whom were ≤ 5 years of age. No drug‐associated adverse events were observed. The numbers of functional CYP2C19 alleles per subject in the cohort were 2 (n = 25), 1 (n = 11), and 0 (n = 1). Pharmacokinetic parameters (mean ± SD, range) were as follows: tmax (2.1 ± 1.2, 1–6 h), Cmax (331.1 ± 333.6,20.8–885.8 ng/mL), AUC0 → ∞ (809.5 ± 893.8, 236.9–1330.9 ng/mL•h), t1/2 (0.98 ± 0.22, 0.7–1.4h), and CL/F(1.8 ± 1.4, 0.3–5.8 L/h/kg). Comparison of mean AUC0 → ∞ values normalized for dose (i.e., per 1 mg/kg) between subjects with one versus two functional CYP2C19 alleles revealed no statistically significant difference. In addition, the CL/F and apparent elimination rate constant (Λz) for omeprazole were not significantly different for subjects with one versus two functional CYP2C19 alleles. No association between age and CL/F, t1/2, or Λz was observed. The range of t1/2 values for omeprazole was similar to those reported in adults (1–1.5 h). Conclusions: (1) in children ages 2 to 16 years receiving 10 or 20 mg of omeprazole as a single oral dose, the PK are quite comparable to values reported for adults, and (2) in pediatric patients who are CYP2C19 extensive metabolizers, there was no association between genotype and the pharmacokinetics of omeprazole.

Pharmacokinetic Study of Omeprazole in Elderly Healthy Volunteers

SummaryThe pharmacokinetics of omeprazole and its metabolites were studied in 8 healthy elderly volunteers using [14C]omeprazole. In another 6 healthy elderly volunteers, the pharmacokinetics of omeprazole were studied using unlabelled drug. Each volunteer received single doses of omeprazole intravenously (20mg) and orally (40mg) as solutions in a randomised crossover design. The plasma concentrations and urinary excretion of omeprazole and metabolites were followed for 24 and 96h, respectively.The results indicate that the average metabolic capacity of omeprazole is decreased in the elderly compared with that found in earlier studies of healthy young individuals. This was reflected in an increase in bioavailability from 56 to 76%, a reduction in mean systemic clearance by approximately 50% (0.25 L/min) and a prolongation of the mean elimination half-life from 0.7 to 1.0h compared with the young.Despite these findings, the considerable overlap in these parameters between young and old volunteers, together with data from previous pharmacodynamic studies and the wide therapeutic range of omeprazole, indicate that dosage reductions are not needed in the elderly.