Prostaglandin Metabolismand Effects of Inhibitors 3

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For more than 20 years it has been known that prostaglandins, such as PGE

and PGI

(prosta- cyclin), relax the ductus arteriosus (Morris et al. 20003). More recently, it was shown that this effect is mediated via specific receptors, includ- ing prostaglandin EP

and perhaps other G

-cou- pled prostaglandin receptors (

), such as EP

and the prostacyclin receptor IP (Hahn et al. 2000). The significance of prostaglandins for maintenance of ductus patency is exemplified by the delay of ductus closure in COX-2 deficient mice (Baragatti et al. 2003) and by the failure of ductus closure in knockout mice lacking both cyclooxygenase (COX)–1 and COX-2 (Loftin et al.

2002). It is likely but not yet proven in humans that additional mediators are involved in the reg- ulation of ductus tone and remodelling, including nitric oxide (NO) and vascular endothelial growth factor (VEGF) which are also related to prostag- landin metabolism and, therefore, changed after inhibition of prostaglandin generation.

Inhibition of both COX isoforms results in closure of the ductus, the efficacy being depen- dent on gestational age. Several drugs are avai- lable to induce ductus closure in preterm infants,

including indomethacin and ibuprofen, both being non-selective inhibitors of COX-1 and COX-2. However, in particular indomethacin is associated with a number of severe side effects in preterm infants, such as necrotizing enteroco- litis, transient or permanent renal dysfunction, reduction of renal, gastrointestinal and cerebral perfusion and gastrointestinal and intracranial hemorrhage, in particular if the mothers have been pretreated with the compound (tocolysis) (Norton et al. 1993). This might also result in the- rapeutic failure of ductus closure after postnatal treatment. These side effects appear to be less frequent and less severe with ibuprofen at an effi- cacy equal to that of indomethacin. It should also be considered that the half-life of indomethacin and ibuprofen in (preterm) neonates amounts to about 20 and 30 hours, respectively, being about 10 times longer than in adults.

From a pharmacological point of view, the treatment of persisting ductus arteriosus may be improved and requires more detailed knowledge of prostaglandin-related metabolic pathways and their interaction with other pathways in human metabolism.

Prostaglandin Metabolism and Effects of Inhibitors

Karsten Schrör

Biosynthesis and metabolism of prostaglandins ¹³

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⊡ Fig. 3.1 Biosynthesis and metabolism of prostaglandins in humans. Various prostaglandins exist, all sharing a similar chemical structure characterized by 20-carbon unsaturated carboxylic acids with a cyclopentane ring. Arachidonic acid is the precursor not only for prostaglandins but for other chemically related biologically active molecules such as pros- tacyclin, thromboxanes, and leukotrienes. The committed step of prostaglandin biosynthesis, the conversion of arachidonic acid (substrate) to prostaglandin H₂, the common precur- sor for biosynthesis of the various prostanoids, is regulated by the enzyme cyclooxygenase (also termed prostaglandin H synthase). The synthesis of prostaglandin H₂ is the point of differentiation in prostanoid production, with individual cell types possessing predominantly different terminal syn- thases. The terminal synthases generate the various effector

prostaglandins, among which prostaglandin E₂ plays a major role. With regard to the ductus arteriosus, prostaglandin E₂ is essential for maintaining ductus patency in utero. Prosta- glandin E₂ is inactivated to 15-keto-PGE₂ by the nicotinamide adenine dinucleotide-dependent (NAD⁺) enzyme PDGH and than further catabolized. Metabolism of PGE₂ by PGDH cont- ributes to the characteristic fall in PGE₂ levels after birth that are crucial for remodelling of the ductus arteriosus. For a more complete background and synthesis pathways showing the interrelationships among the above compounds, see Camp- bell and Halushka (1996). COX, cyclooxygenase; PGG₂,prosta- glandin endoperoxide; TXA₂, thromboxane; PGI₂, prostacyclin;

PGE₂,prostaglandin E₂; PGD₂, prostaglandin D₂; PGF_2α, prosta- glandin F_2α; PGDH, prostaglandin 15-hydroxyprostaglandin dehydrogenase.

References

Morris JL, Rosen DA, Rosen KR: Nonsteroidal anti-inflammatory agents in neonates. Pediatr Drugs 2003; 5: 385–405.

Hahn EL, He LK, Gamelli RL: Prostaglandin E₂ synthesis and metabolism in burn injury and trauma. J Trauma 2000;

49: 1147–54.

Loftin CD, Tiano HF, Langenbach R: Phenotypes of the COX- deficient mice indicate physiological and pathophysio- logical roles for COX-1 and COX-2. Prostaglandins Other Lipid Mediat 2002; 68–69: 177–85.

Baragatti B, Brizzi F, Ackerley C, Barogi S, Ballou LR, Coceani F:

Cyclooxygenase-1 and cyclooxygenase-2 in the mouse ductus arteriosus: individual activity and functional coup- ling with nitric oxide synthase. Br J Pharmacol 2003; 139:

1505–15.

Norton ME, Merrill J, Cooper BA, Kuller JA, Clyman RI: Neonatal complications after the administration of indomethacin for preterm labor. N Engl J Med 1993; 329: 52–63.

Campbell WB, Halushka PV: Lipid-derived autoacids: Ecosa- noids and platelet-activating factor. In Goodman and Gilman’s the pharmacological basis of therapeutics, 9th edition 1996: 601–616, (eds. Hardman JG et al.), McGraw- Hill, New York, NY.

14 Chapter 3 · Prostaglandin Metabolism and Effects of Inhibitors

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⊡ Fig. 3.2 Prostaglandin E2 synthesis and receptor binding.

Prostaglandin E₂ is synthesized from arachidonic acid via the constitutively expressed cyclooxygenase-1, and the inducible cyclooxygenase-2 enzymes. The bioavailability of arachidonic acid from phospholipids and the activity of phospholipase A₂ regulate prostaglandin production. The inducible cyclooxyge- nase-2 has been localized in many cell types and appears to be activated under conditions of physiologic and pathologic stress. Inflammatory disease states like sepsis induce a cascade of inflammatory and anti-inflammatory mediators that regula- te cyclooxygenase-2 activity and gene expression, thereby leading to elevated plasma concentrations of prostaglandin E₂. This mechanism contributes to the clinical phenomenon of reopening of functionally closed ductuses during infection in preterm infants. Once synthesized, prostaglandin E₂ can exert its multiple effects by interacting with one of four classes of prostaglandin receptors, EP1, EP2, EP3, or EP4. Interactions with these receptors elevate (EP2 and EP4) or depress (EP3) intracellular levels of cAMP or increase intracellular calcium (EP1). PLA₂, phospholipase A₂; COX, cyclooxygenase; COX-1, cyclooxygenase-1; COX-2, cyclooxygenase-2; PGE₂,prostag- landin E₂; EP1, EP2, EP3 and EP4, prostaglandin E2 receptor subtypes; Ca, calcium; cAMP, cyclic adenosine 3’, 5’-mono- phosphate; PGDH, prostaglandin 15-hydroxyprostaglandin dehydrogenase; ASA, aminosalicylic acid; Indo, indomethacin;

Ibu, ibuprofen.