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• W2006827652 abstract "Morbidity is increased in patients undergoing hematopoietic stem cell transplantation when drug–drug interactions lead to unexpected outcomes. These interactions occur as a result of exposure to complicated medical regimens with drugs with narrow therapeutic windows and high toxicity profiles. In this report, we review the available evidence and possible mechanisms of the most clinically relevant drug interactions, including those involving inhibitors and inducers of the P450 isoenzyme system. We identify key interactions that should be familiar to any physician caring for patients after hematopoietic stem cell transplantation. We discuss drug metabolism in children and in the elderly and examine how age-related differences in metabolism make complicate drug regimens in these populations. A better understanding of these interactions and the responsible mechanisms will promote efficient delivery of the safest medical regimens to patients undergoing hematopoietic stem cell transplantation. Morbidity is increased in patients undergoing hematopoietic stem cell transplantation when drug–drug interactions lead to unexpected outcomes. These interactions occur as a result of exposure to complicated medical regimens with drugs with narrow therapeutic windows and high toxicity profiles. In this report, we review the available evidence and possible mechanisms of the most clinically relevant drug interactions, including those involving inhibitors and inducers of the P450 isoenzyme system. We identify key interactions that should be familiar to any physician caring for patients after hematopoietic stem cell transplantation. We discuss drug metabolism in children and in the elderly and examine how age-related differences in metabolism make complicate drug regimens in these populations. A better understanding of these interactions and the responsible mechanisms will promote efficient delivery of the safest medical regimens to patients undergoing hematopoietic stem cell transplantation. Patients undergoing hematopoietic stem cell transplantation (HSCT) are treated with complex medical regimens combining chemotherapeutic, immunosuppressive, and antimicrobial agents, which in various combinations carry the potential for multiple adverse drug–drug interactions. The frequent multiple comorbidities in this patient population, including renal and liver dysfunction, poor nutritional status, and altered protein binding, amplify the risk of clinically significant drug interactions. Literature detailing drug interactions is often difficult to interpret, given the great disparities in how reactions are defined and the widely varying severity of responses among individuals. In addition, although many interactions between pharmacologic agents may be recognized in theory, all of these interactions are not necessarily clinically significant. In this article, we review the drug–drug interactions with which transplantation physicians should be most familiar to reduce adverse events secondary to polypharmacy. We focus primarily on the clinically relevant pharmacokinetic drug interactions that occur in transplantation regimens and offer recommendations for preventing and/or managing those adverse events. Drug interactions may be categorized as either pharmacodynamic or pharmacokinetic based on the mechanism of interaction [1Wilkinson G.R. Drug metabolism and variability among patients in drug response.N Engl J Med. 2005; 352: 2211-2221Crossref PubMed Scopus (503) Google Scholar, 2Hansen P.D. Horn J. Drug Interactions. Analysis and Management. Facts and comparisons. Wolters Kluwer, St Louis2010Google Scholar]. Pharmacodynamic drug interactions result from the physiological activities of two interacting drugs. Pharmacodynamic interactions may be additive, synergistic, or antagonistic and may result in increased or decreased therapeutic and/or adverse effects of a specific drug. Pharmacokinetic drug interactions lead to altered concentrations of a drug or its metabolites resulting from changes in absorption, distribution, metabolism, or elimination. Interactions between two or more drugs may affect any of the stages of drug metabolism. The most common sites of interaction are in the intestinal lumen and liver during CYP450-mediated metabolism. The liver is the site of metabolism for the majority of drugs introduced into the body. It processes medications via mechanisms known as phase I and phase II reactions. During phase I reactions, a functional group is introduced into the fat-soluble substrate, leading to increased solubility in water and more efficient elimination by the kidney. In phase II reactions, the parent drug or the phase I product is conjugated to glucuronic acid or glutathione, leading to a more water-soluble product, which can then be excreted by the kidney or in bile [2Hansen P.D. Horn J. Drug Interactions. Analysis and Management. Facts and comparisons. Wolters Kluwer, St Louis2010Google Scholar]. The isoenzymes of the CYP450 superfamily, which are ubiquitously expressed in the liver and intestinal lumen, are responsible for the majority of phase I reactions. Thus, the most clinically relevant and dangerous interactions involve metabolism mediated by the CYP450 system. More than 50 genes have been identified in humans, but only the following isoenzyme pathways are known to be responsible for the majority of identified metabolic drug interactions: CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. CYP3A4 is the isoform most frequently associated with severe drug interactions, because it is involved in the metabolism of 60% of all drugs in the liver and 70% of all drugs in the intestine [1Wilkinson G.R. Drug metabolism and variability among patients in drug response.N Engl J Med. 2005; 352: 2211-2221Crossref PubMed Scopus (503) Google Scholar]. Mutations in a CYP450 enzyme may lead to a change in normal enzymatic function. These genetic polymorphisms have been described for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5 enzymes. Some of the more common polymorphisms occur in CYP3A5, CYP2C9, and CYP2C19, and each differs among populations and races. The frequency of the CYP3A5∗3 polymorphism is 60% to 70% in Asians and up to 85% to 95% in Caucasians. Approximately 40% of the Caucasian population are carriers of alleles that encode for a partially defective CYP2C9 enzyme, and up to 25% of the Japanese population are poor CYP2C19 metabolizers. Genetic variability can amplify the production of toxic metabolites or inhibit the metabolism of a prodrug, leading to detrimental effects [3Pirmohamed M. Park B.K. Cytochrome P450 enzyme polymorphisms and adverse drug reactions.Toxicology. 2003; 192: 23-32Crossref PubMed Scopus (73) Google Scholar]. Along with genetic variations in drug metabolism are sex-related variations. Women showed a small but significant increase in CYP3A activity, although whether this translates to clinical differences in therapeutic drug effects is unclear [4Greenblatt D.J. von Moltke L.L. Gender has a small but statistically significant effect on clearance of CYP3A substrate drugs.J Clin Pharmacol. 2008; 48: 1350-1355Crossref PubMed Scopus (32) Google Scholar]. CYP-mediated drug interactions can occur by two separate mechanisms: enzyme inhibition and enzyme induction. Inhibition can occur either by direct inactivation or by mutual competition of substrates at a catalytic site. Inhibition of metabolism via the CYP pathway leads to increased peak or trough concentrations and elimination half-lives, increasing the potential for toxic side effects. The onset of inhibition occurs within 1 to 3 days. The extent to which an inhibitor affects the metabolism of another drug depends on factors such as the dosage and the inhibitor’s ability to bind to the enzyme. In theory, drugs metabolized by the same CYP isoenzyme can compete at binding sites for metabolism, possibly leading to altered drug levels. Induction involves increased synthesis or decreased breakdown of CYP isoenzymes. Increased metabolic activity of the CYP system results in decreased plasma levels of the substrate, decreased efficacy, and possibly therapeutic failure of the medication. Induction takes a longer time, with maximal effect occurring over days to weeks [1Wilkinson G.R. Drug metabolism and variability among patients in drug response.N Engl J Med. 2005; 352: 2211-2221Crossref PubMed Scopus (503) Google Scholar, 2Hansen P.D. Horn J. Drug Interactions. Analysis and Management. Facts and comparisons. Wolters Kluwer, St Louis2010Google Scholar]. Another potential mechanism of drug interaction is at the site of membrane transporters. Because the number of binding sites of drug transporters is limited, drug–drug interactions at the binding sites may occur, depending on the drugs’ pharmacokinetic properties. A common transporter involved in drug interactions is P-glycoprotein (P-gp), the product of the multidrug resistance gene (MDR1) present in the kidneys, liver, and endothelial cells of the blood-brain barrier. Administration of a drug that inhibits or induces P-gp can increase or decrease the renal elimination of P-gp substrates and lead to increased or decreased bioavailability in the intestine [1Wilkinson G.R. Drug metabolism and variability among patients in drug response.N Engl J Med. 2005; 352: 2211-2221Crossref PubMed Scopus (503) Google Scholar, 2Hansen P.D. Horn J. Drug Interactions. Analysis and Management. Facts and comparisons. Wolters Kluwer, St Louis2010Google Scholar]. As a result of these interactions in the intestine and liver, presystemic first-pass metabolism is a unique concern for many drugs administered orally. When taken orally, a drug is first absorbed in the gut and then reaches the systemic circulation via the liver. First-pass metabolism occurs in both the gastrointestinal mucosa and the liver. The CYP450 enzyme system in the intestinal mucosa can either inhibit or induce drug metabolism, and the P-gp transporter in the small intestine can act as an efflux pump, presenting a barrier to drug absorption [1Wilkinson G.R. Drug metabolism and variability among patients in drug response.N Engl J Med. 2005; 352: 2211-2221Crossref PubMed Scopus (503) Google Scholar]. Once the drug reaches the liver, a significant portion is oxidized or reduced by hepatic CYP450 metabolizers. To account for first-pass metabolism, many of the drugs used by transplantation physicians require dosage adjustment when changing from the i.v. form to the oral form and vice versa. Drugs that undergo extensive first-pass metabolism in adults include calcineurin inhibitors and fluconazole, among others [2Hansen P.D. Horn J. Drug Interactions. Analysis and Management. Facts and comparisons. Wolters Kluwer, St Louis2010Google Scholar, 5Mihara A. Mori T. Aisa Y. et al.Greater impact of oral fluconazole on drug interaction with intravenous calcineurin inhibitors as compared with intravenous fluconazole.Eur J Clin Pharmacol. 2008; 64: 89-91Crossref PubMed Scopus (12) Google Scholar]. Several chemotherapeutic agents, including busulfan and etoposide, used in conditioning regimens for HSCT are dependent on the CYP450 enzyme system for metabolism to inactive metabolites and elimination. Other agents, such as cyclophosphamide, depend on conversion from a prodrug to an active metabolite to become functional. Based on competition at these sites, drug interactions occurring as early as the conditioning phase of stem cell transplantation are of concern. Busulfan (1,4-bis [methanesulfonyl-y] butane) is a bifunctional alkylating agent that has been used as a conditioning regimen for more than 20 years. Busulfan is metabolized in the liver primarily through a reaction with glutathione-S-transferase (GST) to form a sulfonium ion of glutathione [6Hassan M. Ehrsson H. Metabolism of 14C-busulfan in isolated perfused rat liver.Eur J Drug Metab Pharmacokinet. 1987; 12: 71-76Crossref PubMed Scopus (32) Google Scholar]. Although animal studies have failed to show a role of the CYP450 system in the oxidative metabolism of busulfan, busulfan metabolism is known to be affected by CYP3A4 inducers, such as phenytoin [7Hassan M. Oberg G. Bjorkholm M. et al.Influence of prophylactic anticonvulsant therapy on high-dose busulphan kinetics.Cancer Chemother Pharmacol. 1993; 33: 181-186Crossref PubMed Scopus (82) Google Scholar]. Busulfan has a very narrow therapeutic index, and several studies have shown that toxicity depends on the area under the receiver-operating characteristic curve (AUC) [8Dix S.P. Wingard J.R. Mullins R.E. et al.Association of busulfan area under the curve with veno-occlusive disease following BMT.Bone Marrow Transplant. 1996; 17: 225-230PubMed Google Scholar]. Close pharmacokinetic monitoring is critical when busulfan is administered orally. Oral busulfan is absorbed erratically and is subject to hepatic first-pass metabolism. This can result in low systemic concentrations but high concentrations in the portal-hepatic venous system, which conceivably may contribute to the development of hepatic veno-occlusive disease [8Dix S.P. Wingard J.R. Mullins R.E. et al.Association of busulfan area under the curve with veno-occlusive disease following BMT.Bone Marrow Transplant. 1996; 17: 225-230PubMed Google Scholar]. As a result, many centers have switched to i.v. dosing to reduce pharmacokinetic variability and eliminate cumbersome AUC monitoring [9Lee J.H. Choi S.J. Kim S.E. et al.Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation.Ann Hematol. 2005; 84: 321-330Crossref PubMed Scopus (51) Google Scholar, 10Almog S. Kurnik D. Shimoni A. et al.Linearity and stability of intravenous busulfan pharmacokinetics and the role of glutathione in busulfan elimination.Biol Blood Marrow Transplant. 2011; 17: 117-123Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar]. Caution should be used when administering drugs that compete with busulfan for clearance via the glutathione pathway or interact with the CYP3A4 enzyme system (Table 1) [7Hassan M. Oberg G. Bjorkholm M. et al.Influence of prophylactic anticonvulsant therapy on high-dose busulphan kinetics.Cancer Chemother Pharmacol. 1993; 33: 181-186Crossref PubMed Scopus (82) Google Scholar, 11Buggia I. Zecca M. Alessandrino E.P. et al.GITMO (Gruppo Italiano Trapianto di Midollo Osseo). Itraconazole can increase systemic exposure to busulfan in patients given bone marrow transplantation.Anticancer Res. 1996; 16: 2083-2088PubMed Google Scholar, 12Nilsson C. Aschan J. Hentschke P. et al.The effect of metronidazole on busulfan pharmacokinetics in patients undergoing hematopoietic stem cell transplantation.Bone Marrow Transplant. 2003; 31: 429-435Crossref PubMed Scopus (22) Google Scholar, 13Busulfex [package insert]. ESP Pharma Inc, Edison, NJ2011Google Scholar, 14Murayama N. Imai N. Nakane T. et al.Roles of CYP3A4 and CYP2C19 in methyl hydroxylated and N-oxidized metabolite formation from voriconazole, a new anti-fungal agent, in human liver microsomes.Biochem Pharmacol. 2007; 73: 2020-2026Crossref PubMed Scopus (47) Google Scholar]. The most important interactions include those with phenytoin, acetaminophen, and metronidazole.Table 1Busulfan Drug–Drug InteractionsDrugMechanismEffectRecommendationData TypeAcetaminophenCompetition for glutathioneIncreased busulfan serum levelDo not use 72 hours before or 72 hours after busulfan administration.Theoretical based on metabolism of agents 13Busulfex [package insert]. ESP Pharma Inc, Edison, NJ2011Google ScholarItraconazole, voriconazoleaVoriconazole interaction is theoretical based on the metabolism of the agent by the CYP450 3A4 system [14].Reduced busulfan clearanceIncreased busulfan serum levelUse with caution; monitor for adverse effects of busulfan; consider fluconazole as an alternative.PK, HSCT 11Buggia I. Zecca M. Alessandrino E.P. et al.GITMO (Gruppo Italiano Trapianto di Midollo Osseo). Itraconazole can increase systemic exposure to busulfan in patients given bone marrow transplantation.Anticancer Res. 1996; 16: 2083-2088PubMed Google ScholarMetronidazoleInhibition of CYP3A4; competition for glutathioneIncreased busulfan trough levelDo not use 72 hours before or 72 hours after busulfan administration.PK, prospective HSCT 12Nilsson C. Aschan J. Hentschke P. et al.The effect of metronidazole on busulfan pharmacokinetics in patients undergoing hematopoietic stem cell transplantation.Bone Marrow Transplant. 2003; 31: 429-435Crossref PubMed Scopus (22) Google ScholarPhenytoinInduction of GST and CYP3A4Decreased busulfan plasma level ≥15%Consider using another anticonvulsant; if using phenytoin, monitor AUC of busulfan to guide levels.CR, PK 7Hassan M. Oberg G. Bjorkholm M. et al.Influence of prophylactic anticonvulsant therapy on high-dose busulphan kinetics.Cancer Chemother Pharmacol. 1993; 33: 181-186Crossref PubMed Scopus (82) Google ScholarPK indicates pharmacokinetic studies; CR, case reports.a Voriconazole interaction is theoretical based on the metabolism of the agent by the CYP450 3A4 system 14Murayama N. Imai N. Nakane T. et al.Roles of CYP3A4 and CYP2C19 in methyl hydroxylated and N-oxidized metabolite formation from voriconazole, a new anti-fungal agent, in human liver microsomes.Biochem Pharmacol. 2007; 73: 2020-2026Crossref PubMed Scopus (47) Google Scholar. Open table in a new tab PK indicates pharmacokinetic studies; CR, case reports. Busulfan crosses the blood-brain barrier and can lower the seizure threshold, most frequently with high-dose regimens using every-6-hour dosing. In randomized studies, once-daily dosing had similar pharmacokinetic profiles and transplantation-related complications as every-6-hour dosing [15Madden T. de Lima M. Thapar N. et al.Pharmacokinetics of once-daily intravenous busulfan as part of pretransplantation preparative regimens: a comparison with an every- 6-hour dosing schedule.Biol Blood Marrow Transplant. 2007; 13: 56-64Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar]. For antiseizure prophylaxis, phenytoin historically has been used with the high-dose therapy. In case reports of combined busulfan and phenytoin, busulfan levels were lower than predicted, most likely as a result of induction of both the GST and CYP3A4 systems [7Hassan M. Oberg G. Bjorkholm M. et al.Influence of prophylactic anticonvulsant therapy on high-dose busulphan kinetics.Cancer Chemother Pharmacol. 1993; 33: 181-186Crossref PubMed Scopus (82) Google Scholar]. An alternative agent, such as levetiracetam, is recommended for antiseizure prophylaxis with high-dose busulfan [7Hassan M. Oberg G. Bjorkholm M. et al.Influence of prophylactic anticonvulsant therapy on high-dose busulphan kinetics.Cancer Chemother Pharmacol. 1993; 33: 181-186Crossref PubMed Scopus (82) Google Scholar, 13Busulfex [package insert]. ESP Pharma Inc, Edison, NJ2011Google Scholar]. Possibly through its interaction at the CYP3A4 isoenzyme, metronidazole also interferes with busulfan metabolism, leading to an ∼80% increase in busulfan trough level. Glutathione is thought to act as a scavenger for the reactive metabolites of metronidazole [16Larsson P. Cybulski W. Tjalve H. Binding of 3H-metronidazole in olfactory, respiratory and alimentary epithelia in rats.Pharmacol Toxicol. 1997; 81: 65-73Crossref PubMed Google Scholar]. In a small prospective study of patients undergoing HSCT, patients who received a combination of metronidazole and busulfan showed elevated busulfan levels, elevated liver function test values, and an increased prevalence of veno-occlusive disease compared with those who received busulfan alone [12Nilsson C. Aschan J. Hentschke P. et al.The effect of metronidazole on busulfan pharmacokinetics in patients undergoing hematopoietic stem cell transplantation.Bone Marrow Transplant. 2003; 31: 429-435Crossref PubMed Scopus (22) Google Scholar]. Based on this small study, we do not recommend using these two agents concurrently. When metronidazole is used to treat a known infection, we recommend following similar guidelines as for acetaminophen and starting metronidazole 72 hours after the completion of busulfan therapy [13Busulfex [package insert]. ESP Pharma Inc, Edison, NJ2011Google Scholar]. Acetaminophen is another medication with a theoretical interaction with busulfan. Acetaminophen decreases glutathione levels in blood and tissues and thus has the potential to inhibit the metabolism of busulfan. The manufacturer of Busulfex recommends not administering acetaminophen within 72 hours before starting or completing busulfan therapy, to avoid the risk of myelosuppression, seizure, and veno-occlusive disease [13Busulfex [package insert]. ESP Pharma Inc, Edison, NJ2011Google Scholar]. A recent study examined the stability of the pharmacokinetics of i.v. busulfan combined with fludarabine, a common reduced-intensity conditioning (RIC) regimen for allogeneic HSCT. Two fludarabine-containing RIC regimens were evaluated, and busulfan clearance was determined to be independent of the fludarabine dosage [10Almog S. Kurnik D. Shimoni A. et al.Linearity and stability of intravenous busulfan pharmacokinetics and the role of glutathione in busulfan elimination.Biol Blood Marrow Transplant. 2011; 17: 117-123Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar]. Carmustine (BCNU) is a mustard gas–related α-chloro-nitrosourea compound used as an alkylating agent in chemotherapy and as part of conditioning regimens for autologous HSCT. BCNU is metabolized to both active and inactive species by CYP1A2-mediated enzymes in the liver. The majority of the drug and its metabolites are excreted renally, with 6% to 10% expired as carbon dioxide and 1% eliminated in feces [17Henner W.D. Peters W.P. Eder J.P. et al.Pharmacokinetics and immediate effects of high-dose carmustine in man.Cancer Treat Rep. 1986; 70: 877-880PubMed Google Scholar]. BCNU has very few documented pharmacokinetic drug interactions. A small study found that after the administration of BCNU and cisplatin, patients on oral phenytoin therapy showed decreased serum phenytoin levels [18Grossman S.A. Sheidler V.R. Gilbert M.R. Decreased phenytoin levels in patients receiving chemotherapy.Am J Med. 1989; 87: 505-510Abstract Full Text PDF PubMed Google Scholar]. Based on this finding, the authors recommended close monitoring of phenytoin level when BCNU, and phenytoin are given concurrently, because increases in phenytoin dosage may be necessary during treatment. Alternatively, patients receiving these two drugs could be transitioned to i.v. phenytoin [18Grossman S.A. Sheidler V.R. Gilbert M.R. Decreased phenytoin levels in patients receiving chemotherapy.Am J Med. 1989; 87: 505-510Abstract Full Text PDF PubMed Google Scholar] or given levetiracetam during BCNU therapy. Cyclophosphamide, a cyclic phosphamide ester of mechlorethamine, acts as an alkylating agent and is extensively metabolized in the liver by the CYP450 system (CYP3A4, CYP2A6, CYP2B6, CYP2C8, CYP2C9, and CYP2C19). The parent compound is a prodrug that is not pharmacologically active until converted to its active metabolites, phosphoramide mustard and acrolein. Acrolein is thought to be responsible for cyclophosphamide-induced bladder toxicity. Between 5% and 25% of cyclophosphamide is excreted unchanged in the urine [19Boddy A.V. Yule S.M. Metabolism and pharmacokinetics of oxazaphosphorines.Clin Pharmacokinet. 2000; 38: 291-304Crossref PubMed Google Scholar]. In general, any medication metabolized by one of the aforementioned CYP450 enzymes has the potential for a pharmacokinetic interaction, and concurrent administration should be done with caution. In a retrospective study of 103 patients undergoing HSCT, cyclophosphamide conditioning was associated with decreased cyclosporine serum concentrations for up to 2 weeks after transplantation [20Nagamura F. Takahashi T. Takeuchi M. et al.Effect of cyclophosphamide on serum cyclosporine levels at the conditioning of hematopoietic stem cell transplantation.Bone Marrow Transplant. 2003; 32: 1051-1058Crossref PubMed Scopus (4) Google Scholar]. The authors hypothesized that this interaction was related to the autoinduction of cyclophosphamide, which usually occurs within 24 hours of cyclophosphamide administration. Changes in cyclosporine levels will occur fairly rapidly when the two drugs are used concurrently. We recommend close monitoring of cyclosporine level and appropriate dosage adjustments. Because tacrolimus is also metabolized by the CYP3A4 isoenzyme, concurrent administration with cyclophosphamide carries similar concerns for an interaction. Although there are no published studies confirming this interaction, we believe that it is reasonable to follow tacrolimus levels closely and adjust the dosage appropriately. The antiemetic aprepitant is also a CYP3A4 inhibitor. However, a recent randomized, double-blind placebo-controlled study of 40 patients undergoing HSCT with either cyclophosphamide/busulfan or cyclophosphamide/total body irradiation conditioning exposed to aprepitant or placebo 1 hour before the first chemotherapy or radiation treatment showed no significant changes in cyclophosphamide pharmacokinetics, and chemotherapy-induced nausea and vomiting were well tolerated [21Bubalo J.S. Cherala G. McCune J.S. et al.Aprepitant pharmacokinetics and assessing the impact of aprepitant on cyclophosphamide metabolism in cancer patients undergoing hematopoietic stem cell transplantation.J Clin Pharmacol. 2011; Mar 17; (epub ahead of print)PubMed Google Scholar]. Based on that study, we feel that aprepitant can be used safely with conditioning regimens including cyclophosphamide. Melphalan, synthesized from nitrogen mustard and phenylalanine, is a bifunctional chloroethylating alkylating agent that forms DNA cross-links and undergoes rapid hydrolysis in the plasma to the inactive metabolites monohydroxymelphalan and dihydroxymelphalan. Approximately 20% to 50% of melphalan is eliminated in feces, and 10% is excreted by the kidneys [22Samuels B.L. Bitran J.D. High-dose intravenous melphalan: a review.J Clin Oncol. 1995; 13: 1786-1799PubMed Google Scholar]. Studies demonstrating clinically relevant pharmacokinetic drug–drug interactions for stem cell transplantation physicians are limited. Thiotepa is a polyfunctional alkylating agent of the nitrogen mustard type. Cytoxicity results from the formation of an unstable ethylenimmonium ion, which alkylates intracellular molecular structures, including nucleic acids, leading to disruption of DNA bonds. Thiotepa is metabolized extensively in the liver by CYP2B6 and CYP3A4 to its active metabolite triethylene phosphoramide (tepa), and both thiotepa and tepa are further conjugated to glutathione, which is catalyzed by GST isoenzymes A1-1 and P1-1. Some 85% of thiotepa is excreted largely as metabolites within 72 hours of administration [23Maanen M.J. Smeets C.J. Beijnen J.H. Chemistry, pharmacology and pharmacokinetics of N, N′, N′′ -triethylenethiophosphoramide (ThioTEPA).Cancer Treat Rev. 2000; 26: 257-268Abstract Full Text PDF PubMed Scopus (43) Google Scholar]. Some case reports suggest that drug interactions are related to competition at the CYP3A4 and 2B6 enzymes. Carboplatin is a cisplatin analogue with a mechanism of action similar to that of alkylating agents. Carboplatin is excreted renally, with 60% to 80% eliminated in the first 24 hours after administration. The platinum from degraded carboplatin binds irreversibly to plasma proteins and is eliminated slowly, with an approximate half-life of 5 days [24Duffull S.B. Robinson B.A. Clinical pharmacokinetics and dose optimisation of carboplatin.Clin Pharmacokinet. 1997; 33: 161-183Crossref PubMed Google Scholar]. Studies in patients undergoing HSCT have suggested that dosing based on AUC is more accurate and associated with less hematologic toxicity compared with dosing based on body surface area (BSA) [25Colby C. Koziol S. McAfee S.L. et al.High-dose carboplatin and regimen-related toxicity following autologous bone marrow transplant.Bone Marrow Transplant. 2002; 29: 467-472Crossref PubMed Google Scholar]. In case reports, patients receiving carboplatin and phenytoin had decreased phenytoin levels, leading to recurrent seizures; thus, frequent monitoring of phenytoin levels both during and after treatment is recommended [26Dofferhoff A.S. Berendsen H.H. van den Naalt J. et al.Decreased phenytoin level after carboplatin treatment.Am J Med. 1990; 89: 247-248Abstract Full Text PDF PubMed Google Scholar]. Concomitant administration of carboplatin and aminoglycosides was also associated with hearing loss in several case reports; thus, an alternative antibiotic is recommended during platinum therapy because of concerns about additive ototoxicity [27Parsons S.K. Neault M.W. Lehmann L.E. et al.Severe ototoxicity following carboplatin-containing conditioning regimen for autologous marrow transplantation for neuroblastoma.Bone Marrow Transplant. 1998; 22: 669-674Crossref PubMed Google Scholar]. Etoposide (VP-16) is a semisynthetic podophyllotoxin derivative classified as a topoisomerase II “poison,” the activity of which results in the stabilization of cleavable complexes, causing irreversible DNA damage and cell death in proliferating cells. VP-16 is metabolized in the liver by the CYP450 enzymes, including CYP3A4/3A5 and to O-demethylated metabolites (catechol and quinine) via prostaglandin synthases or myeloperoxidase. Up to 60% of VP-16 is excreted renally unchanged from its original form. Approximately 15% of the drug and its metabolites are eliminated in feces, and 5% undergoes b" @default.
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• W2006827652 title "Important Drug Interactions in Hematopoietic Stem Cell Transplantation: What Every Physician Should Know" @default.
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